scholarly journals Sex-specific Effects of α2δ-1 in the Ventromedial Hypothalamus of Female Mice Controlling Glucose and Lipid Balance

Endocrinology ◽  
2020 ◽  
Vol 161 (7) ◽  
Author(s):  
Jennifer A Felsted ◽  
Alice Meng ◽  
Dominique Ameroso ◽  
Maribel Rios
Keyword(s):  
Glycemic Control ◽  
Balance Control ◽  
Ventromedial Hypothalamus ◽  
Sympathetic Tone ◽  
Chow Diet ◽  
Sexually Dimorphic ◽  
Hypothalamic Region ◽  
Metabolic Alterations ◽  
Female Mice ◽  
Lipid Balance

Abstract The thrombospondin receptor alpha2delta-1 (α2δ-1) plays essential roles promoting the activity of SF1 neurons in the ventromedial hypothalamus (VMH) and mediating glucose and lipid metabolism in male mice. Its role in the VMH of female mice remains to be defined, especially considering that this hypothalamic region is sexually dimorphic. We found that α2δ-1 depletion in SF1 neurons differentially affects glucose and lipid balance control and sympathetic tone in females compared to males. Mutant females show a modest increase in relative body weight gain when fed a high-fat diet (HFD) and normal energy expenditure, indicating that α2δ-1 is not a critical regulator of energy balance in females, similar to males. However, diminished α2δ-1 function in the VMH leads to enhanced glycemic control in females fed a chow diet, in contrast to the glucose intolerance reported previously in mutant males. Interestingly, the effects of α2δ-1 on glucose balance in females are influenced by diet. Accordingly, females but not males lacking α2δ-1 exhibit diminished glycemic control as well as susceptibility to hepatic steatosis when fed a HFD. Increased hepatic sympathetic tone and CD36 mRNA expression and reduced adiponectin levels underlie these diet-induced metabolic alterations in mutant females. The results indicate that α2δ-1 in VMH SF1 neurons critically regulates metabolic function through sexually dimorphic mechanisms. These findings are clinically relevant since metabolic alterations have been reported as a side effect in human patients prescribed gabapentinoid drugs, known to inhibit α2δ-1 function, for the treatment of seizure disorders, neuropathic pain, and anxiety disorders.

scholarly journals Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice

2013 ◽  
Vol 304 (12) ◽  
pp. E1321-E1330 ◽  
Author(s):  
Kazunari Nohara ◽  
Rizwana S. Waraich ◽  
Suhuan Liu ◽  
Mathieu Ferron ◽  
Aurélie Waget ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Intolerance ◽  
Adult Female ◽  
Sympathetic Tone ◽  
Visceral Adiposity ◽  
Androgen Excess ◽  
Altered Expression ◽  
Female Mice ◽  
The Impact

Among women, the polycystic ovarian syndrome (PCOS) is considered a form of metabolic syndrome with reproductive abnormalities. Women with PCOS show increased sympathetic tone, visceral adiposity with enlarged adipocytes, hypoadiponectinemia, insulin resistance, glucose intolerance, increased inactive osteocalcin, and hypertension. Excess fetal exposure to androgens has been hypothesized to play a role in the pathogenesis of PCOS. Previously, we showed that neonatal exposure to the androgen testosterone (NT) programs leptin resistance in adult female mice. Here, we studied the impact of NT on lean and adipose tissues, sympathetic tone in cardiometabolic tissues, and the development of metabolic dysfunction in mice. Neonatally androgenized adult female mice (NTF) displayed masculinization of lean tissues with increased cardiac and skeletal muscle as well as kidney masses. NTF mice showed increased and dysfunctional white adipose tissue with increased sympathetic tone in both visceral and subcutaneous fat as well as increased number of enlarged and insulin-resistant adipocytes that displayed altered expression of developmental genes and hypoadiponectinemia. NTF exhibited dysfunctional brown adipose tissue with increased mass and decreased energy expenditure. They also displayed decreased undercarboxylated and active osteocalcin and were predisposed to obesity during chronic androgen excess. NTF showed increased renal sympathetic tone associated with increased blood pressure, and they developed glucose intolerance and insulin resistance. Thus, developmental exposure to testosterone in female mice programs features of cardiometabolic dysfunction, as can be observed in women with PCOS, including increased sympathetic tone, visceral adiposity, insulin resistance, prediabetes, and hypertension.

The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia

2021 ◽  
Vol 13 (590) ◽  
pp. eabd6434
Author(s):  
Patrick Sweeney ◽  
Michelle N. Bedenbaugh ◽  
Jose Maldonado ◽  
Pauline Pan ◽  
Katelyn Fowler ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
Feeding Behavior ◽  
Critical Role ◽  
Brain Regions ◽  
Sexually Dimorphic ◽  
Male And Female ◽  
Female Mice ◽  
Bidirectional Regulation ◽  
Fear And Anxiety ◽  
Agouti Related Protein

Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of AgRP neurons in bidirectionally controlling feeding, there are currently no therapeutics available specifically targeting this circuitry. The melanocortin-3 receptor (MC3R) is expressed in multiple brain regions and exhibits sexual dimorphism of expression in some of those regions in both mice and humans. MC3R deletion produced multiple forms of sexually dimorphic anorexia that resembled aspects of human anorexia nervosa. However, there was no sexual dimorphism in the expression of MC3R in AgRP neurons, 97% of which expressed MC3R. Chemogenetic manipulation of arcuate MC3R neurons and pharmacologic manipulation of MC3R each exerted potent bidirectional regulation over feeding behavior in male and female mice, whereas global ablation of MC3R-expressing cells produced fatal anorexia. Pharmacological effects of MC3R compounds on feeding were dependent on intact AgRP circuitry in the mice. Thus, the dominant effect of MC3R appears to be the regulation of the AgRP circuitry in both male and female mice, with sexually dimorphic sites playing specialized and subordinate roles in feeding behavior. Therefore, MC3R is a potential therapeutic target for disorders characterized by anorexia, as well as a potential target for weight loss therapeutics.

A prolactin-dependent sexually dimorphic mechanism of migraine chronification

Cephalalgia ◽  
2021 ◽  
pp. 033310242110398
Author(s):  
Daigo Ikegami ◽  
Edita Navratilova ◽  
Xu Yue ◽  
Aubin Moutal ◽  
Caroline M Kopruszinski ◽  
...  
Keyword(s):  
Trigeminal Ganglion ◽  
Medication Overuse ◽  
Medication Overuse Headache ◽  
Nasal Delivery ◽  
Nasal Administration ◽  
Dopamine Receptor Agonist ◽  
Sexually Dimorphic ◽  
Down Regulation ◽  
Female Mice ◽  
Cutaneous Allodynia

Objective Determination of possible sex differences in mechanisms promoting migraine progression and the contribution of prolactin and the prolactin long (PRLR-L) and short (PRLR-S) receptor isoforms. Background The majority of patients with chronic migraine and medication overuse headache are female. Prolactin is present at higher levels in women and increases migraine. Prolactin signaling at the PRLR-S selectively sensitizes nociceptors in female rodents, while expression of the PRLR-L is protective. Methods Medication overuse headache was modeled by repeated sumatriptan administration in male and female mice. Periorbital and hindpaw cutaneous allodynia served as a surrogate of migraine-like pain. PRLR-L and PRLR-S isoforms were measured in the trigeminal ganglion with western blotting. Possible co-localization of PRLR with serotonin 5HT1B and 5HT1D receptors was determined with RNAscope. Cabergoline, a dopamine receptor agonist that inhibits circulating prolactin, was co-administered with sumatriptan. Nasal administration of CRISPR/Cas9 plasmid was used to edit expression of both PRLR isoforms. Results PRLR was co-localized with 5HT1B or 5HT1D receptors in the ophthalmic region of female trigeminal ganglion. A single injection of sumatriptan increased serum PRL levels in female mice. Repeated sumatriptan promoted cutaneous allodynia in both sexes but down-regulated trigeminal ganglion PRLR-L, without altering PRLR-S, only in females. Co-administration of sumatriptan with cabergoline prevented allodynia and down-regulation of PRLR-L only in females. CRISPR/Cas9 editing of both PRLR isoforms in the trigeminal ganglion prevented sumatriptan-induced periorbital allodynia in females. Interpretation We identified a sexually dimorphic mechanism of migraine chronification that involves down-regulation of PRLR-L and increased signaling of circulating prolactin at PRLR-S. These studies reveal a previously unrecognized neuroendocrine mechanism linking the hypothalamus to nociceptor sensitization that increases the risk of migraine pain in females and suggest opportunities for novel sex-specific therapies including gene editing through nasal delivery of CRISPR/Cas9 constructs.

scholarly journals Brown Fat Dnmt3b Deficiency Ameliorates Obesity in Female Mice

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1325
Author(s):  
Fenfen Li ◽  
Xin Cui ◽  
Jia Jing ◽  
Shirong Wang ◽  
Huidong Shi ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Energy Expenditure ◽  
Knockout Mice ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Brown Fat ◽  
Chow Diet ◽  
Female Mice ◽  
Diet Induced Obesity

Obesity results from a chronic energy imbalance due to energy intake exceeding energy expenditure. Activation of brown fat thermogenesis has been shown to combat obesity. Epigenetic regulation, including DNA methylation, has emerged as a key regulator of brown fat thermogenic function. Here we aimed to study the role of Dnmt3b, a DNA methyltransferase involved in de novo DNA methylation, in the regulation of brown fat thermogenesis and obesity. We found that the specific deletion of Dnmt3b in brown fat promotes the thermogenic and mitochondrial program in brown fat, enhances energy expenditure, and decreases adiposity in female mice fed a regular chow diet. With a lean phenotype, the female knockout mice also exhibit increased insulin sensitivity. In addition, Dnmt3b deficiency in brown fat also prevents diet-induced obesity and insulin resistance in female mice. Interestingly, our RNA-seq analysis revealed an upregulation of the PI3K-Akt pathway in the brown fat of female Dnmt3b knockout mice. However, male Dnmt3b knockout mice have no change in their body weight, suggesting the existence of sexual dimorphism in the brown fat Dnmt3b knockout model. Our data demonstrate that Dnmt3b plays an important role in the regulation of brown fat function, energy metabolism and obesity in female mice.

A4512 Subclinical metabolic alterations in rats fed with high-fructose diet are sexually dimorphic

2018 ◽  
Vol 36 ◽  
pp. e21-e22
Author(s):  
Daniel Monleon ◽  
Mercedes Pardo-Tendero ◽  
Jose Manuel Morales ◽  
Remedios Segura ◽  
Ana Diaz ◽  
...  
Keyword(s):  
Sexually Dimorphic ◽  
Metabolic Alterations ◽  
High Fructose Diet ◽  
High Fructose

scholarly journals Sexually Dimorphic Regulation of Gut Microbiota and Body Weight by a Naturally Occurring Flavonoid

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 472-472
Author(s):  
Priyanka Sharma ◽  
Guojun Wu ◽  
Hong Ye ◽  
Yan Y Lam ◽  
Deeptha Kumaraswamy ◽  
...  
Keyword(s):  
Body Weight ◽  
Gut Microbiota ◽  
Intestinal Microbiome ◽  
Sexually Dimorphic ◽  
Female Mice ◽  
Diet Induced Obesity ◽  
Naturally Occurring ◽  
Principal Coordinates ◽  
Brown Adipose ◽  
Microbiota Structure

Abstract Objectives 7,8-Dihydroxyflavone (DHF) is a naturally occurring flavonoid that is being actively investigated as a therapeutic modality in the treatment of neurological disorders. A recent study also indicated that oral DHF supplementation protected female but not male mice from diet-induced obesity. However, the mechanisms underlying this sexually-dimorphic effects of DHF were not known. The aim of the work is to investigate the mechanisms underlying sex-specific effects of flavonoid. Methods Age-matched male and female mice were given ad libitum access to high fat-diet and drinking water containing vehicle or DHF for 12 weeks. Body weights, body composition, food, and water intake, were assessed. Immunohistological analysis, immunohistochemistry staining, plasma triglycerides, plasma bile acids, and hepatic lipids were investigated. Fresh fecal samples were collected, genomic DNA was extracted and hypervariable region V4 of the 16S rRNA gene was amplified. Gut microbiota structure was evaluated using alpha diversity indices and beta diversity distance metrices. Principal coordinates analysis (PCoA) was performed using the R “ape” package to visualize differences in gut microbiota structure between treatment groups along principal coordinates that accounted for most of the variations. Results Oral administration of DHF, remodels the intestinal microbiome of female, but not male, prior to divergence in body weight. This is concomitant with increase in brown adipose tissue thermogenesis, mediated by increased expression of UCP1 and Pgc -1α protecting the female mice from diet-induced obesity. Conclusions This study demonstrates sexually-dimorphic effects of a clinically relevant natural compound. Importantly, it points to a role for sex-dependent remodeling of the intestinal microbiome as a mechanism for weight control in females. Thus, our discoveries pave the way for personalized nutrition strategies that account for sex differences in metabolism. Funding Sources NIH.

Improvement in Glycemic Control in Mice of Different Age Groups

2019 ◽  
Author(s):  
Suhadinie Gamage ◽  
Swetha Peddibhotla ◽  
P. Hemachandra Reddy ◽  
Nikhil V. Dhurandhar ◽  
Vijay Hegde
Keyword(s):  
Blood Glucose ◽  
Glycemic Control ◽  
Glucose Intolerance ◽  
Serum Insulin ◽  
Age Groups ◽  
Tolerance Test ◽  
Chow Diet ◽  
Control Blood Glucose ◽  
Beneficial Effects ◽  
Old Mice

Abstract Aims and Methods The declining ability to control blood glucose with advancement of age is an important health risk factor and may lead to insulin resistance, type-2-diabetes and Alzheimer’s disease. Adenovirus 36(Ad36) improves glycemic control independent of insulin signaling(insulin sparing effect) as evidenced by cell, animal and observational human studies. This property of Ad36 may be useful in correcting aging-related glucose intolerance and related health conditions. Therefore, we determined the effect of Ad36 on glycemic control in older mice, to identify the age group that best responds to Ad36. Six, 12 or 20-month old C57Bl/6 mice on chow diet were each divided into weight-matched groups(mock-infected or Ad36-infected). Body weight was recorded weekly post infection (p.i.) and fasting glucose measured(week 0, 4, 8 and 20 p.i.). Blood glucose and serum insulin were measured during glucose tolerance test(week 0 and 16 p.i.). At week 20 p.i., animals were sacrificed, blood and tissues collected. Results Mice from all age groups showed improvement in glucose clearance post Ad36 infection, but a more profound effect was observed in 6-month old mice compared with mock-infected mice. Under fed conditions though there was no difference in blood glucose at 20 wk p.i., interestingly, Ad36 reduced serum insulin in age groups old mice, compared with control mice. Conclusions These findings suggest Ad36 infected animals improve glycemic control and clear post-prandial gluco00000se increase without increasing insulin secretion in an insulin sparing manner. These beneficial effects provide strong evidence for developing Ad36-based approaches as a novel tool to attenuate age associated glucose intolerance.

scholarly journals Sex-specific differences in neonatal hyperoxic lung injury

2016 ◽  
Vol 311 (2) ◽  
pp. L481-L493 ◽  
Author(s):  
Krithika Lingappan ◽  
Weiwu Jiang ◽  
Lihua Wang ◽  
Bhagavatula Moorthy
Keyword(s):  
Lung Injury ◽  
Lung Development ◽  
Molecular Mechanisms ◽  
Neutrophil Infiltration ◽  
Sexually Dimorphic ◽  
Female Mice ◽  
Hyperoxia Exposure ◽  
Hyperoxic Lung Injury ◽  
Mean Linear Intercept ◽  
Radial Alveolar Count

Male sex is considered an independent predictor for the development of bronchopulmonary dysplasia (BPD) after adjusting for other confounders. BPD is characterized by an arrest in lung development with marked impairment of alveolar septation and vascular development. The reasons underlying sexually dimorphic outcomes in premature neonates are not known. In this investigation, we tested the hypothesis that male neonatal mice will be more susceptible to hyperoxic lung injury and will display larger arrest in lung alveolarization. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia [95% FiO2, postnatal day (PND) 1–5] and euthanized on PND 7 and 21. Extent of alveolarization, pulmonary vascularization, inflammation, and modulation of the NF-κB pathway were determined and compared with room air controls. Macrophage and neutrophil infiltration was significantly increased in hyperoxia-exposed animals but was increased to a larger extent in males compared with females. Lung morphometry showed a higher mean linear intercept (MLI) and a lower radial alveolar count (RAC) and therefore greater arrest in lung development in male mice. This was accompanied by a significant decrease in the expression of markers of angiogenesis (PECAM1 and VEGFR2) in males after hyperoxia exposure compared with females. Interestingly, female mice showed increased activation of the NF-κB pathway in the lungs compared with males. These results support the hypothesis that sex plays a crucial role in hyperoxia-mediated lung injury in this model. Elucidation of the sex-specific molecular mechanisms may aid in the development of novel individualized therapies to prevent/treat BPD.

scholarly journals Towards understanding biology of leydiogioma. G protein-coupled receptor and peroxisome proliferator-activated receptor crosstalk regulates lipid metabolism and steroidogenesis in Leydig cell tumors

2018 ◽  
Author(s):  
Malgorzata Kotula-Balak ◽  
Ewelina Gorowska-Wojtowicz ◽  
Agnieszka Milon ◽  
Piotr Pawlicki ◽  
Alicja Kaminska ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Leydig Cell ◽  
Balance Control ◽  
Regulatory Protein ◽  
Hormone Sensitive Lipase ◽  
Cholesterol Concentration ◽  
Peroxisome Proliferator ◽  
Mouse Tumor ◽  
Lipid Balance ◽  
Leydig Cell Tumors

AbstractLeydig cell tumors (LCT) are the most common type of testicular sex cord-stromal tumor. In this report, we implicate the G-coupled estrogen receptor (GPER) and peroxisome proliferator receptor (PPAR) in regulation of lipid homeostasis and the expression of steroidogenesis-controlling molecules in clinical specimens of LCTs and cell line (mouse tumor Leydig cells; MA-10). We also show the general structure and morphology of human LCTs with the use of scanning electron microscopy and light microscopy, respectively. In LCTs, protein immunoblotting and immunohistochemical analysis revealed increased expression of GPER and decreased expression of PPARα, β and γ. Concomitantly, changes in expression pattern of the lutropin receptor (LHR), protein kinase A (PKA), perilipin (PLIN), hormone sensitive lipase (HSL), steroidogenic acute regulatory protein (StAR), translocator protein (TSPO), HMG-CoA synthase (HMGCA), and HMG-CoA reductase (HMGCR) were observed.Using MA-10 cells treated with GPER and PPAR antagonists (alone and in combination), we demonstrated there is a GPER-PPAR mediated control of cholesterol concentration. In addition, GPER-PPARα regulated estradiol secretion, while GPER-PPARγ affected cGMP concentration. It is assumed that GPER and PPAR can be altered in LCT, resulting in a perturbed lipid balance and steroidogenesis. In LCTs, the phosphatidylinositol-3-kinase (PI3K)-Akt-mTOR signaling pathway was disturbed. Thus, PI3K-Akt-mTOR, together with cGMP, can play a role in LCT proliferation, growth, and metastasis as well as lipid balance control.In conclusion, we discuss the implications of GPER-PPAR interaction with lipid metabolism and steroidogenesis controlling-molecules in LCT biology that can be used in future studies as potential targets of diagnostic and therapeutic implementations.

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