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Molecular Connection between the Endocrine System and Body Regulation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 54258

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Guest Editor
Pediatric Unit, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University of Modena and Reggio Emilia, 41100 Modena, Italy
Interests: diabetes; obesity; cardiovascular disease; dyslipidemia; bone diseases; endocrine systems; endocrine disruptors; endocrine-related tumor and cancer

Special Issue Information

Dear Colleagues,

Communication within the human body involves the transmission of signals to control and coordinate actions in an effort to maintain homeostasis. One of the major organ systems responsible for providing these communication pathways is the endocrine system. In addition to the major endocrine glands, other organs of the body show endocrine function including the hypothalamus, heart, kidneys, gastrointestinal tract, and liver. Moreover, adipose tissue has long been known to produce hormones and pro-inflammatory cytokines while bone-derived hormones play an important role in metabolism. Disruption of the gut microbiota and both inflammatory and metabolic biomarkers affect neuroendocrine homeostasis and promote several peripheral endocrine system diseases.

In this Special Issue of IJMS, we wish to offer a platform for high-quality research and current review articles on the relationship between the endocrine system and body regulation. Moreover, we will highlight recent research and review the role of gut microbiota and metabolic and inflammatory biomarkers in the mechanisms underlying the development of endocrine diseases and their related complications.

Prof. Dr. Barbara Predieri
Guest Editor

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Keywords

  • appetite regulation
  • bone metabolism
  • cardiovascular disease
  • diabetes
  • endocrine system
  • endocrine-related diseases
  • growth and development
  • inflammatory cytokines
  • microbiota
  • obesity

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Published Papers (10 papers)

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20 pages, 4224 KiB  
Article
Fecal Microbiota Transplant in a Pre-Clinical Model of Type 2 Diabetes Mellitus, Obesity and Diabetic Kidney Disease
by Rosana M. C. Bastos, Antônio Simplício-Filho, Christian Sávio-Silva, Luiz Felipe V. Oliveira, Giuliano N. F. Cruz, Eliza H. Sousa, Irene L. Noronha, Cristóvão L. P. Mangueira, Heloísa Quaglierini-Ribeiro, Gleice R. Josefi-Rocha and Érika B. Rangel
Int. J. Mol. Sci. 2022, 23(7), 3842; https://doi.org/10.3390/ijms23073842 - 31 Mar 2022
Cited by 36 | Viewed by 4576
Abstract
Diabetes mellitus (DM) burden encompasses diabetic kidney disease (DKD), the leading cause of end-stage renal disease worldwide. Despite compelling evidence indicating that pharmacological intervention curtails DKD progression, the search for non-pharmacological strategies can identify novel targets for drug development against metabolic diseases. One [...] Read more.
Diabetes mellitus (DM) burden encompasses diabetic kidney disease (DKD), the leading cause of end-stage renal disease worldwide. Despite compelling evidence indicating that pharmacological intervention curtails DKD progression, the search for non-pharmacological strategies can identify novel targets for drug development against metabolic diseases. One of those emergent strategies comprises the modulation of the intestinal microbiota through fecal transplant from healthy donors. This study sought to investigate the benefits of fecal microbiota transplant (FMT) on functional and morphological parameters in a preclinical model of type 2 DM, obesity, and DKD using BTBRob/ob mice. These animals develop hyperglycemia and albuminuria in a time-dependent manner, mimicking DKD in humans. Our main findings unveiled that FMT prevented body weight gain, reduced albuminuria and tumor necrosis factor-α (TNF-α) levels within the ileum and ascending colon, and potentially ameliorated insulin resistance in BTBRob/ob mice. Intestinal structural integrity was maintained. Notably, FMT was associated with the abundance of the succinate-consuming Odoribacteraceae bacteria family throughout the intestine. Collectively, our data pointed out the safety and efficacy of FMT in a preclinical model of type 2 DM, obesity, and DKD. These findings provide a basis for translational research on intestinal microbiota modulation and testing its therapeutic potential combined with current treatment for DM. Full article
(This article belongs to the Special Issue Molecular Connection between the Endocrine System and Body Regulation)
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Figure 1

Figure 1
<p>Intestinal composition analysis by 16S rRNA sequencing in BTBR<sup>ob/ob</sup> FMT (+) and BTBR<sup>ob/ob</sup> FMT (-) mice compared to BTBR WT mice. (<b>A</b>) Bacterial phyla according to 16S rRNA sequencing of 10- and 14-week-old BTBR<sup>ob/ob</sup> FMT (+) and FMT (-) mice compared to age-matched BTBR WT mice: <span class="html-italic">Bacteroidetes</span>, <span class="html-italic">Firmicutes</span>, <span class="html-italic">Proteobacteria</span>, <span class="html-italic">Actinobacteria</span>, <span class="html-italic">Verrucomicrobia</span>, <span class="html-italic">Deferribacteres</span>, and <span class="html-italic">Chloroflex.</span> (<b>B</b>) Alpha diversity analysis by Shannon Index in 10-week-old BTBR WT and age-matched BTBR<sup>ob/ob</sup> mice (<span class="html-italic">p</span> = 0.24), and among 14-week-old BTBR WT <span class="html-italic">versus</span> BTBR<sup>ob/ob</sup> FMT (-) and BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> = 0.21) indicated that the species richness was similar among groups. Results are median and IQR. (<b>C</b>) Principal coordinate analysis (PCoA) based on Bray–Curtis dissimilarity metrics did not show any clearly associated clusters in relation to the study animals. Results are median and IQR. (<b>D</b>) Butyrate producer <span class="html-italic">Lachnospiraceae</span> bacteria family proportions were similar between 10-week-old BTBR WT and age-matched BTBR<sup>ob/ob</sup> mice (<span class="html-italic">p</span> = 0.59), yet higher proportions of these bacteria in 14-week-old BTBR WT compared to 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice (* <span class="html-italic">p</span> = 0.026) were observed. No significant difference was found between 14-week-old BTBR<sup>ob/ob</sup> FMT (+) and FMT (-) mice (<span class="html-italic">p</span> = 0.39). Results are median and IQR. (<b>E</b>,<b>F</b>) Assessment of the differences in relative abundance between genotypes effect evaluated by log 2-fold change demonstrated greater relative abundance in the <span class="html-italic">Gammaproteobacteria</span> and <span class="html-italic">Verrucomicrobiae</span> classes and lower abundance in the <span class="html-italic">Dehalococcoidia</span> and <span class="html-italic">Odoribacteraceae</span> families in 14-week-old BTBR<sup>ob/ob</sup> FMT (-) mice. The treatment increased the abundance of the <span class="html-italic">Odoribacteraceae</span> family in 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice. In all analyses, <span class="html-italic">n</span> = 6/group.</p>
Full article ">Figure 2
<p>Analysis of the functional and metabolic parameters in BTBR<sup>ob/ob</sup> FMT (+) and BTBR<sup>ob/ob</sup> FMT (-) mice compared to BTBR WT mice. (<b>A</b>) BTBR<sup>ob/ob</sup> mice showed significantly higher body weight when compared to BTBR WT mice (*** <span class="html-italic">p</span> = 0.0001); however, 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice at all intervals gained less body weight than BTBR<sup>ob/ob</sup> FMT (-) mice (Row 1: * <span class="html-italic">p</span> = 0.03, Row 2: * <span class="html-italic">p</span> = 0.02, Row 3: * <span class="html-italic">p</span> = 0.02, Row 4: * <span class="html-italic">p</span> = 0.04, Row 5: * <span class="html-italic">p</span> = 0.01). (<b>B</b>) Fasting blood glucose was higher in 10-week-old BTBR<sup>ob/ob</sup> mice when compared to age-matched BTBR WT mice (<span class="html-italic">p</span> = 0.0001), and between 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice when compared to age-matched BTBR WT mice (**** <span class="html-italic">p</span> &lt; 0.0001). No difference was found between 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice (<span class="html-italic">p</span> = 0.78). (<b>C</b>) Glycosuria did not change significantly between 10-week-old BTBR WT and age-matched BTBR<sup>ob/ob</sup> mice (<span class="html-italic">p</span> = 0.59). However, it was higher between 14-week-old BTBR WT and 14-week-old BTBR<sup>ob/ob</sup> FMT (-) (** <span class="html-italic">p</span> = 0.002) and FMT (+) (** <span class="html-italic">p</span> = 0.02) mice, yet with no significant difference between 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice (<span class="html-italic">p</span> &gt; 0.99). (<b>D</b>,<b>E</b>) The body weight of 14-week-old BTBR<sup>ob/ob</sup> FMT (-) mice correlated positively to the <span class="html-italic">Verrucomicrobia</span> phylum (r = 0.9; * <span class="html-italic">p</span> = 0.01) (<b>D</b>) and <span class="html-italic">Flavonifractor</span> genus (r <span class="html-italic">=</span> 0.88 * <span class="html-italic">p =</span> 0.02) (<b>E</b>). (<b>F</b>) Body weight of 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice was positively associated with the intestinal <span class="html-italic">Betaproteobacteria</span> class (r = 0.93, ** <span class="html-italic">p</span> = 0.008). (<b>G</b>) Plasma insulin was elevated in 10-week-old BTBR<sup>ob/ob</sup> when compared to age-matched BTBR WT mice (* <span class="html-italic">p</span> = 0.01) and between 14-week-old BTBR WT mice <span class="html-italic">versus</span> BTBR<sup>ob/ob</sup> FMT (-) mice (* <span class="html-italic">p</span> = 0.02). No significant difference was found between 14-week-old BTBR WT and BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> = 0.3) and 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> &gt; 0.99). (<b>H</b>) Plasma C-peptide was higher in 10-week-old BTBR<sup>ob/ob</sup> mice when compared to age-matched BTBR WT mice (* <span class="html-italic">p</span> = 0.01) and between 14-week-old BTBR WT and BTBR<sup>ob/ob</sup> FMT (-) mice (* <span class="html-italic">p</span> = 0.02). No significant difference was found between 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice (<span class="html-italic">p</span> &gt; 0.05) and 14-week-old BTBR WT and BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> = 0.79). (<b>I</b>) Plasma glucagon did not change significantly between 10-week-old BTBR WT and age-matched BTBR<sup>ob/ob</sup> mice (<span class="html-italic">p</span> = 0.57). However, glucagon levels were higher in 14-week-old BTBR<sup>ob/ob</sup> FMT (-) mice when compared to 14-week-old BTBR WT (* <span class="html-italic">p</span> = 0.02) but not to BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> &gt; 0.99). There was a trend toward higher glucagon levels in BTBR<sup>ob/ob</sup> FMT (+) mice in comparison to age-matched BTBR WT mice (<span class="html-italic">p</span> = 0.05). (<b>J</b>) HOMA-IR in 10-week-old BTBR<sup>ob/ob</sup> was elevated when compared to age-matched BTBR WT mice (* <span class="html-italic">p</span> = 0.02) and between 14-week-old BTBR WT <span class="html-italic">versus</span> BTBR<sup>ob/ob</sup> FMT (-) mice (** <span class="html-italic">p</span> = 0.006). However, no difference was observed between 14-week-old BTBR WT and 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> = 0.2) and between 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice (<span class="html-italic">p</span> &gt; 0.99). (<b>K</b>) HOMA-β was significantly higher in 10-week-old BTBR<sup>ob/ob</sup> when compared to age-matched BTBR WT mice (<span class="html-italic">p</span> = 0.01) and did not change significantly between 14-week-old BTBR WT and BTBR<sup>ob/ob</sup> FMT (-) and BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> = 0.22 and <span class="html-italic">p</span> &gt; 0.99, respectively). All data are means ± SEM. In all analyses, <span class="html-italic">n</span> = 6/group.</p>
Full article ">Figure 3
<p>Analysis of morphological and metabolic parameters in BTBR<sup>ob/ob</sup> FMT (+) and FMT (-) mice compared to BTBR WT mice. (<b>A</b>) Representative hematoxylin-eosin (HE) staining of morphological evaluation of pancreatic islets in 10-week-old BTBR WT compared to age-matched BTBR<sup>ob/ob</sup> mice and 14-week-old BTBR WT compared to BTBR<sup>ob/ob</sup> FMT (+) and FMT (-) mice. Data exhibited hypertrophy of the pancreatic islet in 10-week-old BTBR<sup>ob/ob</sup> mice when compared to age-matched BTBR WT mice (** <span class="html-italic">p</span> = 0.005), and between BTBR<sup>ob/ob</sup> FMT (-) (** <span class="html-italic">p</span> = 0.008) and FMT (+) (* <span class="html-italic">p</span> = 0.01) <span class="html-italic">versus</span> 14-week-old BTBR WT mice. No difference was observed between BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice (<span class="html-italic">p</span> = 0.93). (<b>B</b>) Plasma GLP-1 was significantly more elevated in 10-week-old BTBR<sup>ob/ob</sup> mice when compared to age-matched BTBR WT mice (* <span class="html-italic">p</span> = 0.01) but did not show a significant difference between 14-week-old BTBR WT <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (-) (<span class="html-italic">p</span> = 0.23) and FMT (+) mice (<span class="html-italic">p</span> &gt; 0.99). (<b>C</b>) Plasma GLP-2 was significantly elevated in 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and BTBR<sup>ob/ob</sup> FMT (+) mice when compared to age-matched BTBR WT mice (* <span class="html-italic">p</span> = 0.02 and * <span class="html-italic">p</span> = 0.01, respectively), but no difference was found between BTBR<sup>ob/ob</sup> 14-week-old FMT (-) and FMT (+) mice (<span class="html-italic">p</span> &gt; 0.99). (<b>D</b>) Plasma PYY was significantly different between 14-week-old BTBR WT and 14-week-old BTBR<sup>ob/ob</sup> FMT (-) (* <span class="html-italic">p</span> = 0.02) mice, although no difference was observed between 14-week-old BTBR WT and BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> &gt; 0.99). (<b>E</b>) Plasma GIP was significantly higher in 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and BTBR<sup>ob/ob</sup> FMT (+) mice when compared to age-matched BTBR WT mice (* <span class="html-italic">p</span> = 0.02 for both), but no difference was found between BTBR<sup>ob/ob</sup> 14-week-old FMT (-) and BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> &gt; 0.99). All data are means ± SEM. Scale bars represent 100 µm in (<b>A</b>). In all analyses, <span class="html-italic">n</span> = 5–6/group.</p>
Full article ">Figure 4
<p>Functional and morphological evaluation of the kidney, metagenomics analysis, and systemic inflammatory markers. (<b>A</b>) Urinary albumin-to-creatinine ratio (UACR; μg/mg) was higher in 10-week-old BTBR<sup>ob/ob</sup> mice when compared to the UACR of age-matched BTBR WT mice (** <span class="html-italic">p</span>= 0.006). UACR in 14-week-old BTBR<sup>ob/ob</sup> FMT (-) mice was significantly more elevated when compared to age-matched BTBR WT mice (** <span class="html-italic">p</span> = 0.007). Additionally, UACR in 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice was significantly lower when compared to BTBR<sup>ob/ob</sup> FMT (-) mice (* <span class="html-italic">p</span> = 0.03), and no significant difference was found when compared to 14-week-old BTBR WT mice (<span class="html-italic">p</span> = 0.55). (<b>B</b>) Glomerular filtration rate in accordance with treatment and age: 14-week-old BTBR WT <span class="html-italic">versus</span> BTBR<sup>ob/ob</sup> FMT (-) (<span class="html-italic">p</span> = 0.26), 14-week-old BTBR WT <span class="html-italic">versus</span> BTBR<sup>ob/ob</sup> FMT (+) (<span class="html-italic">p</span> = 0.63), and BTBR<sup>ob/ob</sup> FMT (-) <span class="html-italic">versus</span> FMT (+) mice (<span class="html-italic">p</span>= 0.78). (<b>C</b>,<b>D</b>) UACR of 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice correlated negatively to the <span class="html-italic">Odoribacteraceae</span> family (r = −0.85; <span class="html-italic">p</span> = 0.034) and <span class="html-italic">Deltaproteobacteria</span> class (r = −0.85; <span class="html-italic">p</span> = 0.034). (<b>E</b>) UACR in 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice interacted negatively with the <span class="html-italic">Lactobacillales</span> order (r = −0.9; <span class="html-italic">p</span> = 0.02 and r = −0.89; <span class="html-italic">p</span> = 0.04 respectively). (<b>F</b>) Representative of periodic acid-Schiff (PAS) staining of kidney sections in BTBR WT, BTBR<sup>ob/ob</sup> FMT (-), and FMT (+) mice between 10 and 14 weeks of age. 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice showed an increase in the accumulation of mesangial matrix when compared to age-matched BTBR WT mice (** <span class="html-italic">p</span> = 0.002 for both), and FMT did not prevent that structural damage in 14-week-old BTBR<sup>ob/ob</sup> compared to untreated mice (<span class="html-italic">p</span> = 0.98). (<b>G</b>) Fold change of PDGF expression in the kidney in relation to age-matched BTBR WT: 10-week-old BTBR<sup>ob/ob</sup> mice <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (-) mice was significantly different (* <span class="html-italic">p</span> = 0.02), but no difference was found in 10-week-old BTBR<sup>ob/ob</sup> mice <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> = 0.05), and between 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice (<span class="html-italic">p</span> &gt; 0.99). (<b>H</b>–<b>J</b>) Plasma evaluation of systemic inflammatory markers TNF-α (<b>H</b>), IL-6 (<b>I</b>), and MCP-1 (<b>J</b>) had no significant difference in accordance to the age and treatment (<span class="html-italic">p</span> &gt; 0.99). All data are means ± SEM. Scale bars represent 20 µm in (<b>F</b>). In all analyses, <span class="html-italic">n</span> = 5–6/group.</p>
Full article ">Figure 5
<p>Immunohistochemical analysis of WT-1, total caspase, cleaved caspase-3, and 4-hydroxy-2-noneal (4-HNE) in the kidneys of BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice compared to BTBR WT mice. (<b>A</b>) BTBR<sup>ob/ob</sup> mice exhibited lower detection of WT-1<sup>+</sup> cells in all ages when compared to BTBR WT mice: 10-week-old BTBR<sup>ob/ob</sup> and age-matched BTBR WT mice (** <span class="html-italic">p</span> = 0.004), 14-week-old BTBR WT <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (-) (*** <span class="html-italic">p</span> = 0.0007) and FMT (+) (*** <span class="html-italic">p</span> = 0.0001) mice. FMT did not prevent a decrease in the podocyte number (<span class="html-italic">p</span> = 0.93). (<b>B</b>) Fold change of WT-1 expression in the kidney in relation to age-matched BTBR WT: 10-week-old BTBR<sup>ob/ob</sup> mice <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (-) mice was significantly different (* <span class="html-italic">p</span> = 0.03), but no difference was found in 10-week-old BTBR<sup>ob/ob</sup> mice <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> = 0.16), and between 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice (<span class="html-italic">p</span> = 0.62). (<b>C</b>) Immunohistochemical analysis for lipid-related oxidative stress was not significantly different between 10-week-old and BTBR<sup>ob/ob</sup> and age-matched BTBR WT mice (<span class="html-italic">p</span> = 0.7), and 14-week-old BTBR WT <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (-) mice (<span class="html-italic">p</span> = 0.89), 14-week-old BTBR WT <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> = 0.1), and 14-week-old BTBR<sup>ob/ob</sup> FMT (-) <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> = 0.16). (<b>D</b>) Immunohistochemical analysis for total caspase showed no significant difference according to age and treatment: 10-week-old BTBR<sup>ob/ob</sup> <span class="html-italic">versus</span> age-matched BTBR WT mice (<span class="html-italic">p</span> = 0.7), 14-week-old BTBR WT <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (-) mice (<span class="html-italic">p</span> = 0.09), 14-week-old BTBR WT <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> = 0.57), and 14-week-old BTBR<sup>ob/ob</sup> FMT (-) <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> = 0.85). (<b>E</b>) Immunohistochemical analysis for cleaved caspase-3 showed a significant difference between 10-week-old BTBR<sup>ob/ob</sup> and age-matched BTBR WT mice (* <span class="html-italic">p</span> = 0.03), but no significant difference was found between 14-week-old BTBR WT <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (-) mice (<span class="html-italic">p</span> &gt; 0.99), 14-week-old BTBR WT <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> = 0.99), and 14-week-old BTBR<sup>ob/ob</sup> FMT (-) <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice (<span class="html-italic">p</span> = 0.99). Scale bars represent 10 µm in (<b>A</b>) and 20 µm in (<b>C</b>–<b>E</b>). All data are means ± SEM. In all analyses, <span class="html-italic">n</span> = 5–6/group.</p>
Full article ">Figure 6
<p>Evaluation of gene expression and morphological aspects of intestinal crypts and villi in BTBR<sup>ob/ob</sup> FMT (-) and BTBR<sup>ob/ob</sup> FMT (+) mice compared to BTBR WT mice. (<b>A</b>) Fold change of TNF-α expression in the ileum from age-matched BTBR WT: TNF-α expression of 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice was significantly downregulated when compared to 10-week-old BTBR<sup>ob/ob</sup> mice (** <span class="html-italic">p</span> = 0.004) and 14-week-old BTBR<sup>ob/ob</sup> FMT (-) mice (* <span class="html-italic">p</span> = 0.02). No significant difference was found between 10-week-old BTBR<sup>ob/ob</sup> <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (-) mice (<span class="html-italic">p</span> = 0.76). (<b>B</b>) Representative hematoxylin-eosin (HE) staining of the morphological evaluation of ileum crypts from 10-week-old BTBR<sup>ob/ob</sup> compared to age-matched BTBR WT showed no difference in crypt height (<span class="html-italic">p</span> = 0.08), also from 14-week-old BTBR WT <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (-) (<span class="html-italic">p</span> = 0.49) and FMT (+) (<span class="html-italic">p</span> &gt; 0.99) mice. No difference was observed between 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice (<span class="html-italic">p</span> &gt; 0.99). Furthermore, no difference was found in the villi of this segment in 10-week-old BTBR<sup>ob/ob</sup> mice and age-matched BTBR WT mice (<span class="html-italic">p</span> = 0.16), and between 14-week-old BTBR WT and 14-week-old BTBR<sup>ob/ob</sup> mice FMT (-) (<span class="html-italic">p</span> &gt; 0.99) and FMT (+) (<span class="html-italic">p</span> &gt; 0.99) mice. No difference was observed between 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice (<span class="html-italic">p</span> = 0.99). (<b>C</b>) Fold change of TNF-α expression in the ascending colon relative to age-matched BTBR WT: TNF-α expression of 14-week-old BTBR<sup>ob/ob</sup> FMT (+) mice was significantly downregulated when compared to 10-week-old BTBR<sup>ob/ob</sup> mice (** <span class="html-italic">p</span> = 0.0014), but was not significantly different from 14-week-old BTBR<sup>ob/ob</sup> FMT (-) mice (<span class="html-italic">p</span> = 0.1). (<b>D</b>) Representative hematoxylin-eosin (HE) staining from morphological assessment of ascending colon crypts in 10-week-old BTBR<sup>ob/ob</sup> mice and age-matched BTBR WT and 14-week-old BTBR WT mice in comparison to BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice. The data showed no difference in the height of 10-week-old BTBR<sup>ob/ob</sup> crypts when compared to age-matched BTBR WT (<span class="html-italic">p</span> = 0.18) mice and between 14-week-old BTBR WT and 14-week-old BTBR<sup>ob/ob</sup> FMT (-) (<span class="html-italic">p</span> &gt; 0.99) and FMT (+) (<span class="html-italic">p</span> = 0.99) mice. There was no difference between 14-week-old BTBR<sup>ob/ob</sup> FMT (-) and FMT (+) mice (<span class="html-italic">p</span> = 0.99). All data are means ± SEM. Scale bars represent 50 µm in (<b>B</b>) and 20 µm in (<b>D</b>). In all analyses, <span class="html-italic">n</span> = 5–6/group.</p>
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<p>Immunohistochemical evaluation of claudin-1 and occludin proteins in ileum and ascending colon in BTBR<sup>ob/ob</sup> FMT (+) and BTBR<sup>ob/ob</sup> FMT (-) mice compared to BTBR WT mice. (<b>A</b>) Claudin-1 evaluation in the ileum crypts showed no significant difference according to age and treatment (all <span class="html-italic">p</span> &gt; 0.99). Likewise, detection of claudin-1 in ileum villi was not statistically significant: 14-week-old BTBR WT <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (-) (<span class="html-italic">p</span> &gt; 0.99) and BTBR<sup>ob/ob</sup> FMT (+) (<span class="html-italic">p</span> = 0.97) mice, and 14-week-old BTBR<sup>ob/ob</sup> FMT (-) <span class="html-italic">versus</span> FMT (+) (<span class="html-italic">p</span> = 0.99) mice. (<b>B</b>) Claudin-1 expression in ascending colon crypts was not different among mice, regardless of age and treatment (all <span class="html-italic">p</span> &gt; 0.99). (<b>C</b>) Occludin expression in ileum crypts was not significantly different between 14-week-old BTBR WT <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (-) (<span class="html-italic">p</span> = 0.79) and FMT (+) (<span class="html-italic">p</span> &gt; 0.99) mice, and 14-week-old BTBR<sup>ob/ob</sup> FMT (-) <span class="html-italic">versus</span> FMT (+) (<span class="html-italic">p</span> &gt; 0.99) mice. In ileum villi, occludin expression was not different between 14-week-old BTBR WT <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT(-) and FMT (+) (<span class="html-italic">p</span> &gt; 0.99 for both) mice, and 14-week-old BTBR<sup>ob/ob</sup> FMT(-) <span class="html-italic">versus</span> FMT (+) (<span class="html-italic">p</span> &gt; 0.99) mice. (<b>D</b>) Occludin expression in the ascending colon crypt was significantly different between 10-week-old BTBR<sup>ob/ob</sup> and age-matched BTBR WT mice (* <span class="html-italic">p</span> = 0.01), but not significantly different between 14-week-old BTBR WT <span class="html-italic">versus</span> 14-week-old BTBR<sup>ob/ob</sup> FMT (-) (<span class="html-italic">p</span> = 0.06) and FMT (+) (<span class="html-italic">p</span> = 0.27) mice, and 14-week-old BTBR<sup>ob/ob</sup> FMT (-) <span class="html-italic">versus</span> FMT (+) (<span class="html-italic">p</span> = 0.96) mice. All data are means ± SEM. Scale bars represent 100 µm in (<b>A</b>–<b>D</b>). All data are means ± SEM. In all analyses, <span class="html-italic">n</span> = 4–6/group.</p>
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13 pages, 1744 KiB  
Article
Neurosecretory Protein GL Accelerates Liver Steatosis in Mice Fed Medium-Fat/Medium-Fructose Diet
by Yuki Narimatsu, Eiko Iwakoshi-Ukena, Mana Naito, Shogo Moriwaki, Megumi Furumitsu and Kazuyoshi Ukena
Int. J. Mol. Sci. 2022, 23(4), 2071; https://doi.org/10.3390/ijms23042071 - 13 Feb 2022
Cited by 5 | Viewed by 2083
Abstract
Sugar consumption can readily lead to obesity and metabolic diseases such as liver steatosis. We previously demonstrated that a novel hypothalamic neuropeptide, neurosecretory protein GL (NPGL), promotes fat accumulation due to the ingestion of sugar by rats. However, differences in lipogenic efficiency of [...] Read more.
Sugar consumption can readily lead to obesity and metabolic diseases such as liver steatosis. We previously demonstrated that a novel hypothalamic neuropeptide, neurosecretory protein GL (NPGL), promotes fat accumulation due to the ingestion of sugar by rats. However, differences in lipogenic efficiency of sugar types by NPGL remain unclear. The present study aimed to elucidate the obesogenic effects of NPGL on mice fed different sugars (i.e., sucrose or fructose). We overexpressed the NPGL-precursor gene (Npgl) in the hypothalamus of mice fed a medium-fat/medium-sucrose diet (MFSD) or a medium-fat/medium-fructose diet (MFFD). Food intake and body mass were measured for 28 days. Body composition and mRNA expression of lipid metabolic factors were measured at the endpoint. Npgl overexpression potently increased body mass with fat accumulation in the white adipose tissue of mice fed MFFD, although it did not markedly affect food intake. In contrast, we observed profound fat deposition in the livers of mice fed MFFD but not MFSD. In the liver, the mRNA expression of glucose and lipid metabolic factors was affected in mice fed MFFD. Hence, NPGL induced liver steatosis in mice fed a fructose-rich diet. Full article
(This article belongs to the Special Issue Molecular Connection between the Endocrine System and Body Regulation)
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Figure 1

Figure 1
<p>Effects of <span class="html-italic">Npgl</span> overexpression on food intake, body mass, and food efficiency. The panels show the data obtained after injection of AAV-CTL or AAV-NPGL into mice fed MFSD or MFFD for 28 days. (<b>A</b>) Cumulative food intake at all points. (<b>B</b>) Cumulative food intake 28 days after injection. (<b>C</b>) Body mass at all points. (<b>D</b>) Body mass 28 days after injection. (<b>E</b>) Food efficiency expressed as body weight gain per cumulative food intake per week at all points. (<b>F</b>) Food efficiency 28 days after injection. Each value represents the mean ± standard error of the mean (<span class="html-italic">n</span> = 5–6/group). * <span class="html-italic">p</span> &lt; 0.05, *** <span class="html-italic">p</span> &lt; 0.005 AAV-CTL (MFSD) vs. AAV-NPGL (MFSD) in the same period by one-way ANOVA with Tukey’s test for multiple comparisons, <sup>†</sup> <span class="html-italic">p</span> &lt; 0.05, <sup>††</sup> <span class="html-italic">p</span> &lt; 0.01, <sup>†††</sup> <span class="html-italic">p</span> &lt; 0.005 AAV-CTL (MFFD) vs. AAV-NPGL (MFFD) in the same period by one-way ANOVA with Tukey’s test for multiple comparisons, <sup>‡‡‡</sup> <span class="html-italic">p</span> &lt; 0.005 AAV-CTL (MFSD) vs. AAV-NPGL (MFSD) by two-way ANOVA by repeated measures with Bonferroni’s test for multiple comparisons, <sup>§§§</sup> <span class="html-italic">p</span> &lt; 0.005 AAV-CTL (MFFD) vs. AAV-NPGL (MFFD) by two-way ANOVA by repeated measures with Bonferroni’s test for multiple comparisons. NPGL, neurosecretory protein GL; AAV-CTL, AAV-based control vector; AAV-NPGL, AAV-based NPGL-precursor gene vector; MFSD, medium-fat/medium-sucrose diet; MFFD, medium-fat/medium-fructose diet.</p>
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<p>Effects of <span class="html-italic">Npgl</span> overexpression on fat accumulation. The panels show the data obtained after injection of AAV-CTL or AAV-NPGL into mice fed MFSD or MFFD for 28 days. (<b>A</b>) Mass of the inguinal, epididymal, retroperitoneal, and perirenal WAT. (<b>B</b>) Representative images of sections of the inguinal WAT of mice fed MFSD or MFFD. Scale bars = 100 µm. Each value represents the mean ± standard error of the mean (<span class="html-italic">n</span> = 5–6). Differences between groups were assessed by one-way ANOVA with Tukey’s test for multiple comparisons. * <span class="html-italic">p</span> &lt; 0.05 AAV-CTL (MFSD) vs. AAV-NPGL (MFSD), <sup>††</sup> <span class="html-italic">p</span> &lt; 0.01, <sup>†††</sup> <span class="html-italic">p</span> &lt; 0.005 AAV-CTL (MFFD) vs. AAV-NPGL (MFFD). NPGL, neurosecretory protein GL; AAV-CTL, AAV-based control vector; AAV-NPGL, AAV-based NPGL-precursor gene vector; MFSD, medium-fat/medium-sucrose diet; MFFD, medium-fat/medium-fructose diet; WAT, white adipose tissue.</p>
Full article ">Figure 3
<p>Effects of <span class="html-italic">Npgl</span> overexpression on muscles and organs. The panels show the data obtained after injection of AAV-CTL or AAV-NPGL into mice fed MFSD or MFFD for 28 days. (<b>A</b>) Mass of the gastrocnemius muscle. (<b>B</b>) Mass of the testis, liver, kidney, and heart. (<b>C</b>) Representative liver sections stained using Oil Red O in mice fed MFSD or MFFD. Scale bars = 100 µm. Each value represents the mean ± standard error of the mean (<span class="html-italic">n</span> = 5–6). Differences between groups were assessed by one-way ANOVA with Tukey’s test for multiple comparisons. <sup>††</sup> <span class="html-italic">p</span> &lt; 0.01 AAV-CTL (MFFD) vs. AAV-NPGL (MFFD). NPGL, neurosecretory protein GL; AAV-CTL, AAV-based control vector; AAV-NPGL, AAV-based NPGL-precursor gene vector; MFSD, medium-fat/medium-sucrose diet; MFFD, medium-fat/medium-fructose diet.</p>
Full article ">Figure 4
<p>Effects of <span class="html-italic">Npgl</span> overexpression on serum parameters. The panels show the data obtained after injection of AAV-CTL or AAV-NPGL into mice fed MFSD or MFFD for 28 days. (<b>A</b>) Serum level of glucose. (<b>B</b>) Serum level of insulin. (<b>C</b>) Serum level of triglyceride. (<b>D</b>) Serum level of free fatty acids. (<b>E</b>) Serum level of cholesterol. Each value represents the mean ± standard error of the mean (<span class="html-italic">n</span> = 5–6). Differences between groups were assessed by one-way ANOVA with Tukey’s test for multiple comparisons. * <span class="html-italic">p</span> &lt; 0.05 AAV-CTL (MFSD) vs. AAV-NPGL (MFSD). NPGL, neurosecretory protein GL; AAV-CTL, AAV-based control vector; AAV-NPGL, AAV-based NPGL-precursor gene vector; MFSD, medium-fat/medium-sucrose diet; MFFD, medium-fat/medium-fructose diet.</p>
Full article ">Figure 5
<p>Effects of <span class="html-italic">Npgl</span> overexpression on the mRNA expression of lipid metabolism-related genes. The panels show the data obtained after injection of AAV-CTL or AAV-NPGL into mice fed MFSD or MFFD for 28 days. (<b>A</b>) mRNA expression in iWAT. (<b>B</b>) Hepatic mRNA expression. Each value represents the mean ± standard error of the mean (<span class="html-italic">n</span> = 5–6). Differences between groups were assessed by one-way ANOVA with Tukey’s test for multiple comparisons. <sup>||</sup> <span class="html-italic">p</span> &lt; 0.05, <sup>||||</sup> <span class="html-italic">p</span> &lt; 0.01 AAV-NPGL (MFSD) vs. AAV-NPGL (MFFD). NPGL, neurosecretory protein GL; AAV-CTL, AAV-based control vector; AAV-NPGL, AAV-based NPGL-precursor gene vector; MFSD, medium-fat/medium-sucrose diet; MFFD, medium-fat/medium-fructose diet; WAT, white adipose tissue; iWAT, inguinal WAT.</p>
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19 pages, 6499 KiB  
Article
Architecture of the Pancreatic Islets and Endocrine Cell Arrangement in the Embryonic Pancreas of the Grass Snake (Natrix natrix L.). Immunocytochemical Studies and 3D Reconstructions
by Magdalena Kowalska and Weronika Rupik
Int. J. Mol. Sci. 2021, 22(14), 7601; https://doi.org/10.3390/ijms22147601 - 16 Jul 2021
Cited by 2 | Viewed by 4229
Abstract
During the early developmental stages of grass snakes, within the differentiating pancreas, cords of endocrine cells are formed. They differentiate into agglomerates of large islets flanked throughout subsequent developmental stages by small groups of endocrine cells forming islets. The islets are located within [...] Read more.
During the early developmental stages of grass snakes, within the differentiating pancreas, cords of endocrine cells are formed. They differentiate into agglomerates of large islets flanked throughout subsequent developmental stages by small groups of endocrine cells forming islets. The islets are located within the cephalic part of the dorsal pancreas. At the end of the embryonic period, the pancreatic islet agglomerates branch off, and as a result of their remodeling, surround the splenic “bulb”. The stage of pancreatic endocrine ring formation is the first step in formation of intrasplenic islets characteristics for the adult specimens of the grass snake. The arrangement of endocrine cells within islets changes during pancreas differentiation. Initially, the core of islets formed from B and D cells is surrounded by a cluster of A cells. Subsequently, A, B, and D endocrine cells are mixed throughout the islets. Before grass snake hatching, A and B endocrine cells are intermingled within the islets, but D cells are arranged centrally. Moreover, the pancreatic polypeptide (PP) cells are not found within the embryonic pancreas of the grass snake. Variation in the proportions of different cell types, depending on the part of the pancreas, may affect the islet function—a higher proportion of glucagon cells is beneficial for insulin secretion. Full article
(This article belongs to the Special Issue Molecular Connection between the Endocrine System and Body Regulation)
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Figure 1

Figure 1
<p>Transverse sections through the grass snake embryo body (<b>A</b>) and pancreas (<b>B</b>–<b>D</b>) at developmental stages I–III. (<b>A</b>–<b>C</b>) Sections stained with phloxine and gallocyanin. (<b>A</b>) Scale bar = 100 μm. (<b>B</b>) Magnification of the frame in (<b>A</b>). (<b>B</b>,<b>C</b>) Note agglomerations of endocrine cells near the spleen anlage. Scale bar = 20 μm. (<b>D</b>) Section stained with methylene blue. Scale bar = 20 μm Abbreviations: G: gut; Li: liver; P: pancreas; Sp: spleen; arrowhead—endocrine cell.</p>
Full article ">Figure 2
<p>Transverse sections through the pancreas of the grass snake embryo at developmental stages IV–VIII stained with phloxine and gallocyanin (<b>A</b>,<b>B</b>) and methylene blue (<b>C</b>). (<b>A</b>) Scale bar = 100 μm. (<b>B</b>,<b>C</b>) Scale bar = 20 μm. (<b>B</b>) Magnification of the frame in (<b>A</b>). Note presumptive islets. Abbreviations: G: gut; P: pancreas; Sp: spleen.</p>
Full article ">Figure 3
<p>Transverse sections through the pancreas of the grass snake embryos at developmental stages IX–XI stained with phloxine and gallocyanin (<b>A</b>,<b>B</b>,<b>D</b>,<b>E</b>) and methylene blue (<b>F</b>). (<b>A</b>) Section through the most cephalic part of the pancreas. Scale bar = 100 μm. (<b>B</b>) Note splenic “bulb”. Scale bar = 100 μm. (<b>C</b>) Note connecting pancreatic islets. Scale bar = 20 μm. (<b>D</b>) Pancreatic islets forming ring around the splenic “bulb”. Scale bar = 100 μm (<b>E</b>) Small pancreatic islets within more caudal part of the dorsal pancreas. Scale bar = 100 μm. (<b>F</b>) Pancreatic islets forming large cords. Scale bar = 10 μm Abbreviations: P: pancreas; Sp: spleen; asterisk—pancreatic islets.</p>
Full article ">Figure 4
<p>Longitudinal sections through the pancreas of the grass snake embryos at developmental stages IX–XI stained with phloxine and gallocyanin (<b>A</b>,<b>B</b>) and methylene blue (<b>C</b>). (<b>A</b>,<b>B</b>) note large pancreatic islets in the cephalic part of the dorsal pancreas. (<b>A</b>) Scale bar = 200 μm. (<b>B</b>) Scale bar = 50 μm. (<b>C</b>) Scale bar = 50 μm. Abbreviations: P: pancreas; Sp: spleen; asterisk—pancreatic islets.</p>
Full article ">Figure 5
<p>3D reconstructions of the endocrine tissue arrangement within pancreas of the grass snake embryos at developmental stages I–III. Note that endocrine tissue is localized only in the dorsal part of pancreas. (<b>A</b>) Bottom view. Pancreas with spleen visualized. (<b>B</b>) Top view. Only pancreas visualized. (<b>C</b>) Lateral view with spleen and pancreas. (<b>D</b>) Lateral view with pancreas. (<b>E</b>) Top view with spleen and pancreas. (<b>F</b>) Top view with pancreas.</p>
Full article ">Figure 6
<p>3D reconstructions of the pancreatic islet arrangement within pancreas of the grass snake embryos at developmental stages IV–VIII. Note large agglomerate of endocrine tissue. (<b>A</b>) Lateral view. Pancreas with spleen visualized. (<b>B</b>) Lateral view on pancreatic islets. (<b>C</b>) Anterio-lateral view. (<b>D</b>) Anterio-lateral view on pancreatic islets.</p>
Full article ">Figure 7
<p>3D reconstructions of the pancreatic islet arrangement within pancreas of the grass snake embryos at developmental stages IX–XI. (<b>A</b>–<b>C</b>,<b>E</b>) lateral view, (<b>D</b>,<b>F</b>) top view. Note ring forming by pancreatic islets and splenic “bulb”.</p>
Full article ">Figure 8
<p>Arrangement of three main pancreatic hormones (glucagon, insulin, and somatostatin) within the pancreas of the grass snake embryos at subsequent developmental stages. (<b>A</b>,<b>D</b>,<b>G</b>,<b>J</b>,<b>M</b>) Fluorescence for glucagon. (<b>B</b>,<b>E</b>,<b>H,K,N</b>) Fluorescence for insulin. (<b>C</b>,<b>F</b>,<b>I</b>,<b>L</b>,<b>O</b>) Fluorescence for somatostatin. Scale bars—50 µm.</p>
Full article ">Figure 9
<p>Arrangement of pancreatic endocrine hormone producing cells within pancreatic islets of the grass snake embryos at time of hatching. (<b>A</b>,<b>B</b>) Note that the A and B cells are often intermingled. (<b>C</b>) PP cells are not present within embryonic pancreas of studied species. (<b>D</b>) Large islets of A cells in more caudal part of the dorsal pancreas. (<b>E</b>) Single A cells present in the most caudal part of the dorsal pancreas. Scale bars—50 µm.</p>
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14 pages, 1269 KiB  
Article
Placental Glucose Transporters and Response to Bisphenol A in Pregnancies from of Normal and Overweight Mothers
by Leonardo Ermini, Anna Maria Nuzzo, Francesca Ietta, Roberta Romagnoli, Laura Moretti, Bianca Masturzo, Luana Paulesu and Alessandro Rolfo
Int. J. Mol. Sci. 2021, 22(12), 6625; https://doi.org/10.3390/ijms22126625 - 21 Jun 2021
Cited by 10 | Viewed by 3137
Abstract
Bisphenol A (BPA) is a synthetic phenol extensively used in the manufacture of polycarbonate plastics and epoxy resins and a component of liquid and food storages. Among health disorders potentially attributed to BPA, the effects on metabolism have been especially studied. BPA represents [...] Read more.
Bisphenol A (BPA) is a synthetic phenol extensively used in the manufacture of polycarbonate plastics and epoxy resins and a component of liquid and food storages. Among health disorders potentially attributed to BPA, the effects on metabolism have been especially studied. BPA represents a hazard in prenatal life because of its presence in tissues and fluids during pregnancy. Our recent study in rats fed with BPA showed a placental increase in glucose type 1 transporter (GLUT-1), suggesting a higher uptake of glucose. However, the role of BPA on GLUT transporters in pregnant women with metabolic dysfunction has not yet been investigated. In this study, placental tissue from 26 overweight (OW) women and 32 age-matched normal weight (NW) pregnant women were examined for expression of GLUT1 and GLUT4. Placental explants from OW and NW mothers were exposed to BPA 1 nM and 1 μM and tested for GLUTs expression. The data showed a different response of placental explants to BPA in GLUT1 expression with an increase in NW mothers and a decrease in OW ones. GLUT4 expression was lower in the explants from OW than NW mothers, while no difference was showed between OW and NW in placental biopsies for any of the transporters. Full article
(This article belongs to the Special Issue Molecular Connection between the Endocrine System and Body Regulation)
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Graphical abstract

Graphical abstract
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<p>Glut 1 and 4 expression (<b>A</b>,<b>C</b>) and protein levels (<b>B</b>,<b>D</b>) in placenta from normal (<b>CTRL</b>) and overweight (<b>OW</b>) women. (<b>A</b>) qPCR analysis of GLUT1 mRNA in normal (<span class="html-italic">n</span> = 32) and overweight (<span class="html-italic">n</span> = 26) placental tissue. (<b>B</b>) Representative WB (high panel) and corresponding densitometry (low panel) of GLUT1 in placenta from CTRL (<span class="html-italic">n</span> = 12) and OW (<span class="html-italic">n</span> = 18) women. (<b>C</b>) qPCR analysis of GLUT4 mRNA in normal (<span class="html-italic">n</span> = 26) and overweight (<span class="html-italic">n</span> = 25) placental tissue. (<b>D</b>) Representative WB (high panel) and corresponding densitometry (low panel) of GLUT4 in placenta from CTRL (<span class="html-italic">n</span> = 12) and OW (<span class="html-italic">n</span> = 18) women. Data are presented as mean ±ES.</p>
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<p>GLUT 1 and 4 expression (<b>A</b>,<b>C</b>) and protein levels (<b>B</b>,<b>D</b>) in placenta explants from normal (<b>CTRL</b>) and overweight (<b>OW</b>) women. (<b>A</b>) Fold Change of GLUT1 mRNA in normal (<span class="html-italic">n</span> = 3) and overweight (<span class="html-italic">n</span> = 5) placental explants. (<b>B</b>) Representative WB (left panel) and corresponding densitometry (right panel) of GLUT1 in placenta explants from CTRL (<span class="html-italic">n</span> = 6) and OW (<span class="html-italic">n</span> = 5) women. (<b>C</b>) Fold Change of GLUT4 mRNA in normal (<span class="html-italic">n</span> = 3) and overweight (<span class="html-italic">n</span> = 5) placental explants. (<b>D</b>) Representative WB (left panel) and corresponding densitometry (right panel) of GLUT4 in placenta explants from CTRL (<span class="html-italic">n</span> = 6) and OW (<span class="html-italic">n</span> = 5) women. Data are presented as mean ±ES. Significance was determined using an unpaired two-sided <span class="html-italic">t</span>-test. * <span class="html-italic">p</span> &lt; 0.05.</p>
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<p>GLUT 1 and 4 expressions (<b>A</b>,<b>C</b>) and protein levels (<b>B</b>,<b>D</b>) in placenta explants treated with BPA from control pregnancy. (<b>A</b>) Fold Change of GLUT1 mRNA in placental explants from NW women (<span class="html-italic">n</span> = 3) treated with BPA 1 nM and BPA 1 μM compared to the vehicle as control. (<b>B</b>) Representative WB (left panel) and corresponding densitometry (right panel) of GLUT1 in placental explants from NW women (<span class="html-italic">n</span> = 4) treated with BPA 1 nM and BPA 1 μM compared to the vehicle as control. (<b>C</b>) Fold Change of GLUT4 mRNA in placental explants from NW women (<span class="html-italic">n</span> = 3) treated with BPA 1 nM and BPA 1 μM compared to the vehicle as control. (<b>D</b>) Representative WB (left panel) and corresponding densitometry (right panel) of GLUT4 in placental explants from NW women (<span class="html-italic">n</span> = 4) treated with BPA 1 nM and BPA 1 μM compared to the vehicle as control. Data are presented as mean ±ES. Significance was determined using a one-way ANOVA and Bonferroni’s test for post hoc comparisons * <span class="html-italic">p</span> &lt; 0.05. Ct: control.</p>
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<p>GLUT 1 and 4 expressions (<b>A</b>,<b>C</b>) and protein levels (<b>B</b>,<b>D</b>) in placenta explants treated with BPA from overweight women. (<b>A</b>) Fold Change of GLUT1 mRNA in placental explants from OW women (<span class="html-italic">n</span> = 5) treated with BPA 1 nM and BPA 1 μM compared to the vehicle as control. (<b>B</b>) Representative WB (left panel) and corresponding densitometry (right panel) of GLUT1 in placental explants from OW women (<span class="html-italic">n</span> = 6) treated with BPA 1 nM and BPA 1 μM compared to the vehicle as control. (<b>C</b>) Fold Change of GLUT4 mRNA in placental explants from OW women (<span class="html-italic">n</span> = 5) treated with BPA 1 nM and BPA 1 μM compared to the vehicle as control. (<b>D</b>) Representative WB (left panel) and corresponding densitometry (right panel) of GLUT4 in placental explants from OW women (<span class="html-italic">n</span> = 6) treated with BPA 1 nM and BPA 1 μM compared to the vehicle as control. Data are presented as mean ±ES. Significance was determined using a one-way ANOVA and Bonferroni’s test for post hoc comparisons * <span class="html-italic">p</span> &lt; 0.05. Ct: control.</p>
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15 pages, 2977 KiB  
Article
Nuclear Magnetic Resonance Therapy Modulates the miRNA Profile in Human Primary OA Chondrocytes and Antagonizes Inflammation in Tc28/2a Cells
by Bibiane Steinecker-Frohnwieser, Birgit Lohberger, Nicole Eck, Anda Mann, Cornelia Kratschmann, Andreas Leithner, Werner Kullich and Lukas Weigl
Int. J. Mol. Sci. 2021, 22(11), 5959; https://doi.org/10.3390/ijms22115959 - 31 May 2021
Cited by 10 | Viewed by 3636
Abstract
Nuclear magnetic resonance therapy (NMRT) is discussed as a participant in repair processes regarding cartilage and as an influence in pain signaling. To substantiate the application of NMRT, the underlying mechanisms at the cellular level were studied. In this study microRNA (miR) was [...] Read more.
Nuclear magnetic resonance therapy (NMRT) is discussed as a participant in repair processes regarding cartilage and as an influence in pain signaling. To substantiate the application of NMRT, the underlying mechanisms at the cellular level were studied. In this study microRNA (miR) was extracted from human primary healthy and osteoarthritis (OA) chondrocytes after NMR treatment and was sequenced by the Ion PI Hi-Q™ Sequencing 200 system. In addition, T/C-28a2 chondrocytes grown under hypoxic conditions were studied for IL-1β induced changes in expression on RNA and protein level. HDAC activity an NAD(+)/NADH was measured by luminescence detection. In OA chondrocytes miR-106a, miR-27a, miR-34b, miR-365a and miR-424 were downregulated. This downregulation was reversed by NMRT. miR-365a-5p is known to directly target HDAC and NF-ĸB, and a decrease in HDAC activity by NMRT was detected. NAD+/NADH was reduced by NMR treatment in OA chondrocytes. Under hypoxic conditions NMRT changed the expression profile of HIF1, HIF2, IGF2, MMP3, MMP13, and RUNX1. We conclude that NMRT changes the miR profile and modulates the HDAC and the NAD(+)/NADH signaling in human chondrocytes. These findings underline once more that NMRT counteracts IL-1β induced changes by reducing catabolic effects, thereby decreasing inflammatory mechanisms under OA by changing NF-ĸB signaling. Full article
(This article belongs to the Special Issue Molecular Connection between the Endocrine System and Body Regulation)
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<p>(<b>A</b>) Principal component analysis (PCA) based on all detected miRs of all tested samples distinguishes between healthy (HC) and OA chondrocytes; KO: untreated, KS: NMRT 5 h (<span class="html-italic">n</span> = 3); x-axis: x[, 1] principle component 1; y-axis: x[, 2] principle component 2. (<b>B</b>) Volcano plot representing log2 fold change as a function of the adjusted <span class="html-italic">p</span>-value for miR expression in HC versus OA chondrocytes independent of the treatment procedure. The upregulated and downregulated miRs with the highest fold change are particularly designated. The log 1.5-fold change for direct NMRT effects on HC (<b>C</b>) or OA (<b>D</b>), and especially for miR-106a (<b>E</b>) is presented in heat maps with significance of changes at least at the <span class="html-italic">p</span> &lt; 0.05 level (Student’s <span class="html-italic">t</span>-test). The direct effect of NMRT on HC (grey bars) and OA cells (blue bar) concerning miR-106 expression is depicted (<b>F</b>) (untreated cells as calibrator). The bar chart represents the relative gene expression of miRNAs affected under OA and involved in NF-kB signaling by attempting the comparison of HC and OA cells (grey bars); the blue bars present NMRT induced reversed effects when HC cells were compared with OA cells (blue bars) (<b>G</b>); in both cases HC cells functioned as calibrator. Data are mean ± SEM (<span class="html-italic">n</span> = 5) are given; the Student’s <span class="html-italic">t</span>-test functioned as the statistical analysis. *: <span class="html-italic">p</span> &lt; 0.05 and **: <span class="html-italic">p</span> &lt; 0.01.</p>
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<p>Influence of NMRT on HDAC, COX2 and CDK4 phosphorylation. NMRT induced changes in the expression of HDAC4 and COX2 (<b>A</b>,<b>D</b>) and the activity (R.L.U., relative luminescence units) of HDAC I/II (<b>B</b>) in control (HC) and OA cells are shown. (<b>A</b>) summarizes the NMRT induced changes in expression of HC and OA cells (untreated cells functioned as calibrators). Concentration response curve for the inhibition of HDACI/II activity by trichostatin (nM) with or without NMRT treatment in (<b>C</b>) (<span class="html-italic">n</span> = 3). The box-plot in D represents the difference in expression of HDAC4/COX2 of OA cells (OA) or OA cells treated with NMRT (OA<sup>NMRT</sup>) compared to HC (HC untreated functioned as calibrator; HC/OA; HC/OA<sup>NMRT</sup>); treated OA cells were further compared with NMRT treated HC cells leading to HC<sup>NMRT</sup>/OA<sup>NMRT</sup> (HC<sup>NMRT</sup> cells as calibrator); <span class="html-italic">n</span> = 4 and each experiment was executed in duplicates. Significant changes compared to the respective calibrator are given: *: <span class="html-italic">p</span> &lt; 0.021 and **: <span class="html-italic">p</span> = 0.004. CDK4 phosphorylation by western blotting and phospho-CDK4 normalization to CDK4 is shown (<b>E</b>). The statistical significance for the bar charts and inhibitor study was evaluated by using the Student’s <span class="html-italic">t</span>-test while the differences in median values represented by the box-plots were calculated via the Mann–Whitney Rank Sum test; *: <span class="html-italic">p</span> &lt; 0,05; **: <span class="html-italic">p</span> &lt; 0,01.</p>
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<p>NAD<sup>(+)</sup> and NADH induced luminescence in HC and OA cells with and without NMR treatment. Box plots with the 5th/95th percentile for HC and OA cells ± NMRT (<span class="html-italic">n</span> = 6) (<b>A</b>) and the IL-1β induced change under these conditions (<b>B</b>) are given. The significant effect by IL-1b in HC cells is indicated by *; # depicts the significant difference between IL-1β effect in HC and OA as well as OA and OA NMRT treated cells. The statistical significances for (<b>A</b>,<b>B</b>) were evaluated by using the Mann–Whitney Rank Sum Test; the red lines comply with the mean values. NAD<sup>(+)</sup> and NADH individual measurements are shown (<b>C</b>) as well as the NAD<sup>(+)</sup>/NADH ratio in the presence of IL-1β and NMR treatment is being demonstrated (<b>D</b>) (<span class="html-italic">n</span> = 3). * is the level of significance for NMRT on HC cells, #: significant difference between IL-1β effect in HC and OA as well as OA and OA NMRT treated measured by the two tailed Student’s <span class="html-italic">t</span>-test; *,#: <span class="html-italic">p</span>&lt;0.05; ##: <span class="html-italic">p</span>&lt;0.01; ###: <span class="html-italic">p</span>&lt;0.001.</p>
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<p>Evaluation of hypoxia induced changes in expression within the chondrocyte test system. The bar chart represents the averaged ∆CT values of specific targets under normoxic and hypoxic conditions (<b>A</b>). Statistically significant differences, evaluated by the Student’s <span class="html-italic">t</span>-test, are labeled (*: <span class="html-italic">p</span> &lt; 0.05; **: <span class="html-italic">p</span> &lt; 0.01; ***: <span class="html-italic">p</span> &lt; 0.001). Detailed picture of the change in expression induced by O<sub>2</sub> depletion as ratio (2<sup>−∆∆Ct</sup>) is given within a boxplot–calibrators were cells under normoxic conditions (<b>B</b>). Statistical difference was evaluated by the Mann–Whitney Rank Sum Test; *: <span class="html-italic">p</span> = 0.029, ***: <span class="html-italic">p</span> &lt; 0.001. <span class="html-italic">n</span> = 4, measures is duplicates.</p>
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<p>NMRT modulation in the expression of relevant genes in T/C-28a2 cells, the difference between untreated and treated cells is indicated; level of significance (*. <span class="html-italic">p</span> &lt; 0.05, <span class="html-italic">n</span> = 4) Student’s <span class="html-italic">t</span>-test (<b>A</b>). Effects of IL-1β/TNFα on the expression of HIF1, HIF2, IGF2, MMP3, MMP13, and RUNX1 are given as change in expression ratio (2<sup>−∆∆Ct</sup>) (<b>B</b>–<b>G</b>); significant changes are depicted (*) and were calculated via the Student’s <span class="html-italic">t</span>-test (*: <span class="html-italic">p</span> &lt; 0.05; **: <span class="html-italic">p</span> &lt; 0.01 and ***: <span class="html-italic">p</span> &lt; 0.001). For HIF1, IGF2, and MMP3 the significance of the IL-1β/TNFα ratio between control and NMRT treatment is outlined by hash tags (#: <span class="html-italic">p</span> &lt; 0.05, ##: <span class="html-italic">p</span> &lt; 0.01).</p>
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<p>Schematic description of miRs influencing inflammation and NF-ĸB signaling and the gateways where NMRT might interfere. MiRs are listed and their capacity in controlling gene expression under normal conditions as described in the literature and can be deduced from our results, is depicted by the grey T bar. Repression of miRs in OA chondrocytes (OA↓) can intensify inflammation and NF-ĸB activity (red arrows) while these effects were counteracted by NMRT (signed in green); improvements by NMRT are also presented (NMRT↑). The connection between miR-365 and HDAC4 is marked in blue.</p>
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15 pages, 1049 KiB  
Article
Maternal Heat Stress Alters Expression of Genes Associated with Nutrient Transport Activity and Metabolism in Female Placentae from Mid-Gestating Pigs
by Weicheng Zhao, Fan Liu, Christina D. Marth, Mark P. Green, Hieu H. Le, Brian J. Leury, Alan W. Bell, Frank R. Dunshea and Jeremy J. Cottrell
Int. J. Mol. Sci. 2021, 22(8), 4147; https://doi.org/10.3390/ijms22084147 - 16 Apr 2021
Cited by 20 | Viewed by 3303
Abstract
Placental insufficiency is a known consequence of maternal heat stress during gestation in farm animals. The molecular regulation of placentae during the stress response is little known in pigs. This study aims to identify differential gene expression in pig placentae caused by maternal [...] Read more.
Placental insufficiency is a known consequence of maternal heat stress during gestation in farm animals. The molecular regulation of placentae during the stress response is little known in pigs. This study aims to identify differential gene expression in pig placentae caused by maternal heat exposure during early to mid-gestation. RNA sequencing (RNA-seq) was performed on female placental samples from pregnant pigs exposed to thermoneutral control (CON; constant 20 °C; n = 5) or cyclic heat stress (HS; cyclic 28 to 33 °C; n = 5) conditions between d40 and d60 of gestation. On d60 of gestation, placental efficiency (fetal/placental weight) was decreased (p = 0.023) by maternal HS. A total of 169 genes were differentially expressed (FDR ≤ 0.1) between CON and HS placentae of female fetuses, of which 35 genes were upregulated and 134 genes were downregulated by maternal HS. The current data revealed transport activity (FDR = 0.027), glycoprotein biosynthetic process (FDR = 0.044), and carbohydrate metabolic process (FDR = 0.049) among the terms enriched by the downregulated genes (HS vs. CON). In addition, solute carrier (SLC)-mediated transmembrane transport (FDR = 0.008) and glycosaminoglycan biosynthesis (FDR = 0.027), which modulates placental stroma synthesis, were identified among the pathways enriched by the downregulated genes. These findings provide evidence that heat-stress induced placental inefficiency may be underpinned by altered expression of genes associated with placental nutrient transport capacity and metabolism. A further understanding of the molecular mechanism contributes to the identification of placental gene signatures of summer infertility in pigs. Full article
(This article belongs to the Special Issue Molecular Connection between the Endocrine System and Body Regulation)
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<p>Volcano plot of the differentially expressed genes (DEGs) in female placentae. Blue, red, and grey dots denote downregulated ((FDR (false discovery rate) ≤ 0.1), upregulated (FDR ≤ 0.1), and non-differentially expressed (FDR &gt; 0.1) genes in heat stress placentae (<span class="html-italic">n</span> = 5) compared to control placentae (<span class="html-italic">n</span> = 5). Gene symbols associated with placental transport activity are labelled.</p>
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<p>Functional classification of differentially expressed genes in placentae between heat stress (<span class="html-italic">n</span> = 5) and control (<span class="html-italic">n</span> = 5) groups in the gene ontology (GO) domains of (<b>A</b>) Molecular function, (<b>B</b>) Biological process and (<b>C</b>) Protein class.</p>
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<p>Gene ontology (GO) terms significantly enriched (FDR ≤ 0.05) by the downregulated genes in heat stress placentae (<span class="html-italic">n</span> = 5) compared to control placentae (<span class="html-italic">n</span> = 5) in the GO domains of (<b>A</b>) Molecular function, (<b>B</b>) Biological process and (<b>C</b>) Cellular component. Fold enrichment: No. genes observed in the gene list/No. genes expected.</p>
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<p>Relative protein expression of glucose transporter 2 (GLUT2; (<b>A</b>)) and peptide transporter 1 (PEPT1; (<b>B</b>)) in placentae between control (CON, <span class="html-italic">n</span> = 5) and heat stress (HS, <span class="html-italic">n</span> = 5) groups. Target protein expression was normalised to total protein loaded and expressed as normalised signals (arbitrary units). * <span class="html-italic">p</span> &lt; 0.05. Error bars: standard error of the means.</p>
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Review

Jump to: Research

43 pages, 2425 KiB  
Review
Endocrine Disrupting Chemicals’ Effects in Children: What We Know and What We Need to Learn?
by Barbara Predieri, Lorenzo Iughetti, Sergio Bernasconi and Maria Elisabeth Street
Int. J. Mol. Sci. 2022, 23(19), 11899; https://doi.org/10.3390/ijms231911899 - 7 Oct 2022
Cited by 39 | Viewed by 8580
Abstract
Thousands of natural or manufactured chemicals were defined as endocrine-disrupting chemicals (EDCs) because they can interfere with hormone activity and the endocrine system. We summarize and discuss what we know and what we still need to learn about EDCs’ pathogenic mechanisms of action, [...] Read more.
Thousands of natural or manufactured chemicals were defined as endocrine-disrupting chemicals (EDCs) because they can interfere with hormone activity and the endocrine system. We summarize and discuss what we know and what we still need to learn about EDCs’ pathogenic mechanisms of action, as well as the effects of the most common EDCs on endocrine system health in childhood. The MEDLINE database (PubMed) was searched on 13 May 2022, filtering for EDCs, endocrine diseases, and children. EDCs are a group of compounds with high heterogeneity, but usually disrupt the endocrine system by mimicking or interfering with natural hormones or interfering with the body’s hormonal balance through other mechanisms. Individual EDCs were studied in detail, while humans’ “cocktail effect” is still unclear. In utero, early postnatal life, and/or pubertal development are highly susceptible periods to exposure. Human epidemiological studies suggest that EDCs affect prenatal growth, thyroid function, glucose metabolism, obesity, puberty, and fertility through several mechanisms. Further studies are needed to clarify which EDCs can mainly act on epigenetic processes. A better understanding of EDCs’ effects on human health is crucial to developing future regulatory strategies to prevent exposure and ensure the health of children today, in future generations, and in the environment. Full article
(This article belongs to the Special Issue Molecular Connection between the Endocrine System and Body Regulation)
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<p>In utero, early postnatal life, and/or pubertal development are periods highly susceptible to EDCs’ exposure, leading to human health effects and susceptibility to a wide range of diseases and disorders through several mechanisms of action.</p>
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<p>Mechanism of action of EDCs. (<b>1</b>) EDCs can directly bind to NHRs acting as (A) agonists inducing the gene expression or as (B) antagonists inhibiting the receptor activity; (<b>2</b>) EDCs can affect NHRs function by induction of (A) receptor degradation through proteasome activation, (B) competition for coAct recruitment, and (C) DNA-binding competition; (<b>3</b>) EDCs can dysregulate hormone metabolism, mainly inducing degradation of steroid hormones. Abbreviations: AhR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; coAct, co-activators; coRe, co-repressors; CYP, cytochrome P450; EDCs, endocrine-disrupting chemicals; iXRE, inhibitory XRE; NHRs, nuclear hormone receptors; NREs, NHR response elements; Ub, ubiquitin; XRE, xenobiotic responsive element.</p>
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<p>Literature search and studies’ selection: PRISMA flow diagram [<a href="#B285-ijms-23-11899" class="html-bibr">285</a>].</p>
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22 pages, 3679 KiB  
Review
The Role of Cannabinoids in Bone Metabolism: A New Perspective for Bone Disorders
by Federica Saponaro, Rebecca Ferrisi, Francesca Gado, Beatrice Polini, Alessandro Saba, Clementina Manera and Grazia Chiellini
Int. J. Mol. Sci. 2021, 22(22), 12374; https://doi.org/10.3390/ijms222212374 - 16 Nov 2021
Cited by 10 | Viewed by 5685
Abstract
Novel interest has arisen in recent years regarding bone, which is a very complex and dynamic tissue deputed to several functions ranging from mechanical and protective support to hematopoiesis and calcium homeostasis maintenance. In order to address these tasks, a very refined, continuous [...] Read more.
Novel interest has arisen in recent years regarding bone, which is a very complex and dynamic tissue deputed to several functions ranging from mechanical and protective support to hematopoiesis and calcium homeostasis maintenance. In order to address these tasks, a very refined, continuous remodeling process needs to occur involving the coordinated action of different types of bone cells: osteoblasts (OBs), which have the capacity to produce newly formed bone, and osteoclasts (OCs), which can remove old bone. Bone remodeling is a highly regulated process that requires many hormones and messenger molecules, both at the systemic and the local level. The whole picture is still not fully understood, and the role of novel actors, such as the components of the endocannabinoids system (ECS), including endogenous cannabinoid ligands (ECs), cannabinoid receptors (CBRs), and the enzymes responsible for endogenous ligand synthesis and breakdown, is extremely intriguing. This article reviews the connection between the ECS and skeletal health, supporting the potential use of cannabinoid receptor ligands for the treatment of bone diseases associated with accelerated osteoclastic bone resorption, including osteoporosis and bone metastasis. Full article
(This article belongs to the Special Issue Molecular Connection between the Endocrine System and Body Regulation)
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<p>Bone remodeling process. OBs express RANK-L which promotes osteoclastogenesis following its binding with specific receptor RANK onto the OCs precursors’ surface. This binding induces the maturation of preosteoclasts into mature OCs, resulting in resorption of bone tissue and the release of growth factors. OBs also produce osteoprotegerin (OPG), which acts as a decoy receptor for RANK-L, inhibiting OC formation by blocking RANK-L binding to RANK and stimulating OCs to induce apoptosis. The OPG/RANK-L ratio is a better indicator of bone remodeling status: a high ratio represents bone formation, while a low ratio favors bone resorption.</p>
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<p>Structures of the main endocannabinoids (ECs).</p>
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<p>A schematic overview of the skeletal ECS. Right panel shows endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG), which are found in the bone microenvironment. Endocannabinoid receptors CB1, CB2, and TRPV1 are located on osteoblast and osteoclast cell membranes. Left panel shows the sympathetic innervation of bone. Axons from dorsal root ganglion neurons travel to periosteum and cortical bone. Postganglionic synaptic structures synthesize endocannabinoids on demand and release these lipophilic compounds into the synaptic cleft, where they travel in a retrograde direction to bind to membrane receptors found on osteoblasts and osteoclasts. Osteoblasts and osteoclasts contain enzymes for endocannabinoid synthesis (NAPE, NAPE-PLD, and DAGL) and degradation (FAAH and MAGL). AEA is degraded by FAAH into arachidonate and ethanolamine, whereas 2-AG is metabolized by MAGL into arachidonate and diacylglycerol (DAG).</p>
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<p>Structures of ECS synthetic modulators studied in bone diseases.</p>
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<p>An overview of the “vicious cycle” balance in CIBD. Cancer cells release several factors that stimulate OBs to secrete RANKL. The over-expression of RANKL in OBs drives osteoclast-mediated bone resorption and the consequent release of numerous survival factors, such as insulin-like growth factor 1 (IGF-1) and transforming growth factor beta (TGF-β), which in turn promote the survival and proliferation of tumor cells, thus potentiating cancer spread and bone destruction.</p>
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21 pages, 579 KiB  
Review
The Role of the Noradrenergic System in Eating Disorders: A Systematic Review
by Jacopo Pruccoli, Antonia Parmeggiani, Duccio Maria Cordelli and Marcello Lanari
Int. J. Mol. Sci. 2021, 22(20), 11086; https://doi.org/10.3390/ijms222011086 - 14 Oct 2021
Cited by 13 | Viewed by 4496
Abstract
Noradrenaline (NE) is a catecholamine acting as both a neurotransmitter and a hormone, with relevant effects in modulating feeding behavior and satiety. Several studies have assessed the relationship between the noradrenergic system and Eating Disorders (EDs). This systematic review aims to report the [...] Read more.
Noradrenaline (NE) is a catecholamine acting as both a neurotransmitter and a hormone, with relevant effects in modulating feeding behavior and satiety. Several studies have assessed the relationship between the noradrenergic system and Eating Disorders (EDs). This systematic review aims to report the existing literature on the role of the noradrenergic system in the development and treatment of EDs. A total of 35 studies were included. Preclinical studies demonstrated an involvement of the noradrenergic pathways in binge-like behaviors. Genetic studies on polymorphisms in genes coding for NE transporters and regulating enzymes have shown conflicting evidence. Clinical studies have reported non-unanimous evidence for the existence of absolute alterations in plasma NE values in patients with Anorexia Nervosa (AN) and Bulimia Nervosa (BN). Pharmacological studies have documented the efficacy of noradrenaline-modulating therapies in the treatment of BN and Binge Eating Disorder (BED). Insufficient evidence was found concerning the noradrenergic-mediated genetics of BED and BN, and psychopharmacological treatments targeting the noradrenergic system in AN. According to these data, further studies are required to expand the existing knowledge on the noradrenergic system as a potential target for treatments of EDs. Full article
(This article belongs to the Special Issue Molecular Connection between the Endocrine System and Body Regulation)
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<p>Pathways of the biosynthesis of catecholamines.</p>
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<p>Flowchart of the study.</p>
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17 pages, 883 KiB  
Review
Insulin Signal Transduction Perturbations in Insulin Resistance
by Mariyam Khalid, Juma Alkaabi, Moien A. B. Khan and Abdu Adem
Int. J. Mol. Sci. 2021, 22(16), 8590; https://doi.org/10.3390/ijms22168590 - 10 Aug 2021
Cited by 103 | Viewed by 11560
Abstract
Type 2 diabetes mellitus is a widespread medical condition, characterized by high blood glucose and inadequate insulin action, which leads to insulin resistance. Insulin resistance in insulin-responsive tissues precedes the onset of pancreatic β-cell dysfunction. Multiple molecular and pathophysiological mechanisms are involved in [...] Read more.
Type 2 diabetes mellitus is a widespread medical condition, characterized by high blood glucose and inadequate insulin action, which leads to insulin resistance. Insulin resistance in insulin-responsive tissues precedes the onset of pancreatic β-cell dysfunction. Multiple molecular and pathophysiological mechanisms are involved in insulin resistance. Insulin resistance is a consequence of a complex combination of metabolic disorders, lipotoxicity, glucotoxicity, and inflammation. There is ample evidence linking different mechanistic approaches as the cause of insulin resistance, but no central mechanism is yet described as an underlying reason behind this condition. This review combines and interlinks the defects in the insulin signal transduction pathway of the insulin resistance state with special emphasis on the AGE-RAGE-NF-κB axis. Here, we describe important factors that play a crucial role in the pathogenesis of insulin resistance to provide directionality for the events. The interplay of inflammation and oxidative stress that leads to β-cell decline through the IAPP-RAGE induced β-cell toxicity is also addressed. Overall, by generating a comprehensive overview of the plethora of mechanisms involved in insulin resistance, we focus on the establishment of unifying mechanisms to provide new insights for the future interventions of type 2 diabetes mellitus. Full article
(This article belongs to the Special Issue Molecular Connection between the Endocrine System and Body Regulation)
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Figure 1
<p>Various pathways involved in dysregulation of insulin signaling. Upon insulin binding, insulin receptor gets autophosphorylated. This recruits different substrate adaptors for the signal transduction. The tyrosine phosphorylated IRS1 recruits PI3K, which phosphorylates the serine/threonine residue of protein kinase B (Akt). Akt regulates the translocation of glucose transporter GLUT4 to the cell surface through phosphorylation of the GTPase-activating protein (AS160). Akt promotes glycogen synthesis through inhibition of GSK3 activity and induces protein synthesis via activation of mTOR and downstream elements. Akt phosphorylates and directly inhibits FoxO transcription factors, which inhibits autophagy. The hyperglycemia-induced production of AGE and binding with their receptor RAGE impairs insulin signal transduction by triggering a range of signaling pathways, including JNK, NF-κB, and activation of PKC. The sustained accumulation of AGE depletes the expression of anti-AGE cell surface receptor AGER1, which is responsible for inhibiting the deleterious effects of AGE by competitively interfering with its binding to RAGE. AGER1 along with Sirtuin1 promotes AMPK phosphorylation and activation, which induces GLUT4 gene expression through activation of MEF, GEF transcription factors. The AGE-RAGE induced activation of PKC, NF-κB mediated inflammation, and oxidative stress promotes the serine phosphorylation of IRS, inhibits its action, and induces insulin resistance. AGE: Advanced glycation end products; AGER1: AGE receptor 1 encoded by DDOST gene; AMPK: AMP-activated protein kinase; AS160: Akt substrate of 160 kDa; FoxO: Forkhead family of transcription factors; GLUT4: Glucose transporter protein 4; GEF: GLUT4 enhancer factor; GSK3: Glycogen synthase kinase 3; IKK: IκB kinase; IRS: Insulin receptor substrate1; MEF: Myocyte enhancer factor; mTOR: Mammalian target of rapamycin NF-κB: Nuclear factor κB; PDK1: Phosphoinositide-dependent kinase 1; PI3K: Phosphoinositide 3-kinase; PIP3: Phosphatidylinositol (3,4,5)-trisphosphate; PKC: Protein kinase C; RAGE: Receptor for advanced glycosylation end products; S6K: Ribosomal protein S6 kinase; SREBP: Sterol regulatory element-binding proteins; JNK: c-Jun N-terminal kinase.</p>
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