Sexually different actions of leptin in proopiomelanocortin neurons to regulate glucose homeostasis

Leptin regulates energy balance and glucose homeostasis, at least in part, via activation of receptors in the arcuate nucleus of the hypothalamus located in proopiomelanocortin (POMC) neurons. Females have greater sensitivity to central leptin than males, suggested by a greater anorectic effect of central leptin administration in females. We hypothesized that the regulation of energy balance and peripheral glucose homeostasis of female rodents would be affected to a greater extent than in males if the action of leptin in POMC neurons were disturbed. Male and female mice lacking leptin receptors only in POMC neurons gained significantly more body weight and accumulated more body fat. However, female mice gained disproportionately more visceral adiposity than males, and this appeared to be largely the result of differences in energy expenditure. When maintained on a high-fat diet (HFD), both male and female mutants had higher levels of insulin following exogenous glucose challenges. Chow- and HFD-fed males but not females had abnormal glucose disappearance curves following insulin administrations. Collectively, these data indicate that the action of leptin in POMC neurons is sexually different to influence the regulation of energy balance, fat distribution, and glucose homeostasis.

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Prolonged low-dose dioxin exposure impairs metabolic adaptability to high-fat diet feeding in female but not male mice

10.1101/2020.09.12.294587 ◽

2020 ◽

Author(s):

Geronimo Matteo ◽

Myriam P Hoyeck ◽

Hannah L Blair ◽

Julia Zebarth ◽

Kayleigh RC Rick ◽

...

Keyword(s):

Glucose Homeostasis ◽

High Fat Diet ◽

Plasma Insulin ◽

Low Dose ◽

Dependent Manner ◽

High Fat ◽

Male And Female ◽

Female Mice ◽

Insulin Levels ◽

Plasma Insulin Levels

AbstractObjectiveHuman studies consistently show an association between exposure to persistent organic pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka “dioxin”), and increased diabetes risk. We previously showed that acute high-dose TCDD exposure (20 μg/kg) decreased plasma insulin levels in both male and female mice in vivo; however, effects on glucose homeostasis were sex-dependent. The purpose of this study was to determine whether prolonged exposure to a physiologically relevant dose of TCDD impairs beta cell function and/or glucose homeostasis in a sex-dependent manner in either chow-fed or HFD-fed mice.MethodsMale and female mice were exposed to 20 ng/kg/d TCDD 2x/week for 12 weeks, and simultaneously fed a chow or 45% high-fat diet (HFD). Glucose metabolism was assessed by glucose and insulin tolerance tests throughout the study. Islets were isolated from females at 12 weeks for Tempo-Seq® analysis.ResultsLow-dose TCDD exposure did not lead to adverse metabolic consequences in chow-fed male or female mice, or in HFD-fed males. However, TCDD accelerated the onset of HFD-induced hyperglycemia and impaired glucose-induced plasma insulin levels in female mice. In addition, islet TempO-Seq® analysis showed that TCDD exposure promoted abnormal changes to endocrine and metabolic pathways in HFD-fed females.ConclusionsOur data suggest that TCDD exposure is more deleterious when combined with HFD-feeding in female mice, and that low-dose TCDD exposure increases diabetes susceptibility in females.

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Prolonged low-dose dioxin exposure impairs metabolic adaptability to high-fat diet feeding in female but not male mice

Endocrinology ◽

10.1210/endocr/bqab050 ◽

2021 ◽

Author(s):

Geronimo Matteo ◽

Myriam P Hoyeck ◽

Hannah L Blair ◽

Julia Zebarth ◽

Kayleigh R C Rick ◽

...

Keyword(s):

Glucose Homeostasis ◽

High Fat Diet ◽

Plasma Insulin ◽

Low Dose ◽

High Fat ◽

Male And Female ◽

Female Mice ◽

Insulin Levels ◽

Plasma Insulin Levels

Abstract Objective Human studies consistently show an association between exposure to persistent organic pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka “dioxin”), and increased diabetes risk. We previously showed that a single high-dose TCDD exposure (20 µg/kg) decreased plasma insulin levels in male and female mice in vivo, but effects on glucose homeostasis were sex-dependent. The current study assessed whether prolonged exposure to a physiologically relevant low-dose of TCDD impacts glucose homeostasis and/or the islet phenotype in a sex-dependent manner in chow-fed or high fat diet (HFD)-fed mice. Methods Male and female mice were exposed to 20 ng/kg/d TCDD 2x/week for 12 weeks and simultaneously fed standard chow or a 45% HFD. Glucose homeostasis was assessed by glucose and insulin tolerance tests, and glucose-induced plasma insulin levels were measured in vivo. Histological analysis was performed on pancreas from male and female mice, and islets were isolated from females for Tempo-Seq® analysis. Results Low-dose TCDD exposure did not lead to adverse metabolic consequences in chow-fed male or female mice, or in HFD-fed males. However, TCDD accelerated the onset of HFD-induced hyperglycemia and impaired glucose-induced plasma insulin levels in female mice. TCDD caused a modest increase in islet area in males but reduced % beta cell area within islets in females. RNAseq analysis revealed abnormal changes to endocrine and metabolic pathways in TCDDHFD females. Conclusions Our data suggest that prolonged low-dose TCDD exposure has minimal effects on glucose homeostasis and islet morphology in chow-fed male and female mice, but promotes maladaptive metabolic responses in HFD-fed females.

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Hypothalamic perineuronal nets are regulated by sex and dietary interventions

10.1101/2021.03.07.434286 ◽

2021 ◽

Author(s):

Nan Zhang ◽

Zili Yan ◽

Hailan Liu ◽

Meng Yu ◽

Yang He ◽

...

Keyword(s):

Glucose Homeostasis ◽

High Fat Diet ◽

Intracellular Signaling ◽

Arcuate Nucleus ◽

Gonadal Hormones ◽

Hypothalamic Nucleus ◽

Perineuronal Nets ◽

Dietary Interventions ◽

Female Mice ◽

Specific Manner

ABSTRACTPerineuronal nets (PNNs) are widely present in the hypothalamus, and are thought to provide physical protection and ion buffering for neurons, and regulate their synaptic plasticity and intracellular signaling. Recent evidence indicates that PNNs in the mediobasal hypothalamus plays an important role in the regulation of glucose homeostasis. However, whether and how hypothalamic PNNs are regulated are not fully understood. In the present study, we examined whether PNNs in various hypothalamic regions in mice can be regulated by sex, gonadal hormones, dietary interventions, or their interactions. We demonstrated that gonadal hormones are required to maintain normal PNNs in the arcuate nucleus of hypothalamus in both male and female mice. In addition, PNNs in the terete hypothalamic nucleus display a sexual dimorphism with females higher than males, and high-fat diet feeding increases terete PNNs only in female mice but not in male mice. On the other hand, PNNs in other hypothalamic regions are not influenced by sex, gonadal hormones or dietary interventions. In summary, we demonstrated that hypothalamic PNNs are regulated in a region-specific manner and these results provide a framework to further investigate the potential functions of PNNs in regulating energy/glucose homeostasis at the interplay of sex, gonadal hormones and diets.

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Hypothalamic Perineuronal Nets Are Regulated by Sex and Dietary Interventions

Frontiers in Physiology ◽

10.3389/fphys.2021.714104 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nan Zhang ◽

Zili Yan ◽

Hailan Liu ◽

Meng Yu ◽

Yang He ◽

...

Keyword(s):

Glucose Homeostasis ◽

High Fat Diet ◽

Intracellular Signaling ◽

Arcuate Nucleus ◽

Gonadal Hormones ◽

Hypothalamic Nucleus ◽

Perineuronal Nets ◽

Dietary Interventions ◽

Female Mice ◽

Specific Manner

Perineuronal nets (PNNs) are widely present in the hypothalamus, and are thought to provide physical protection and ion buffering for neurons and regulate their synaptic plasticity and intracellular signaling. Recent evidence indicates that PNNs in the mediobasal hypothalamus play an important role in the regulation of glucose homeostasis. However, whether and how hypothalamic PNNs are regulated are not fully understood. In the present study, we examined whether PNNs in various hypothalamic regions in mice can be regulated by sex, gonadal hormones, dietary interventions, or their interactions. We demonstrated that gonadal hormones are required to maintain normal PNNs in the arcuate nucleus of hypothalamus in both male and female mice. In addition, PNNs in the terete hypothalamic nucleus display a sexual dimorphism with females higher than males, and high-fat diet feeding increases terete PNNs only in female mice but not in male mice. On the other hand, PNNs in other hypothalamic regions are not influenced by sex, gonadal hormones or dietary interventions. In summary, we demonstrated that hypothalamic PNNs are regulated in a region-specific manner and these results provide a framework to further investigate the potential functions of PNNs in regulating energy/glucose homeostasis at the interplay of sex, gonadal hormones and diets.

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Early Life Exposure to Antibiotic Alters Energy Balance during Chronic High-Fat Feeding in Adult Male and Female Mice

Diabetes ◽

10.2337/db18-1999-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1999-P ◽

Cited By ~ 1

Author(s):

HYE LIM NOH ◽

SUJIN SUK ◽

RANDALL H. FRIEDLINE ◽

KUNIKAZU INASHIMA ◽

DUY A. TRAN ◽

...

Keyword(s):

Energy Balance ◽

Adult Male ◽

Early Life ◽

High Fat ◽

Male And Female ◽

Female Mice ◽

Early Life Exposure ◽

Fat Feeding

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Abstract 58: Angiotensin-(1-7) Mas Receptors In The Arcuate Nucleus Of The Hypothalamus Protect Against High Fat Diet-induced Insulin Resistance In Female Mice

Hypertension ◽

10.1161/hyp.78.suppl_1.58 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Darren Mehay ◽

Sarah Bingaman ◽

Yuval Silberman ◽

Amy Arnold

Keyword(s):

Body Composition ◽

Insulin Sensitivity ◽

Energy Balance ◽

Glucose Tolerance ◽

High Fat Diet ◽

Metabolic Regulation ◽

Arcuate Nucleus ◽

Control Diet ◽

High Fat ◽

Metabolic Outcomes

Angiotensin (Ang)-(1-7) is a protective hormone of the renin-angiotensin system that improves insulin sensitivity, glucose tolerance, and energy balance in obese rodents. Our recent findings suggest that Ang-(1-7) activates mas receptors (MasR) in the arcuate nucleus of the hypothalamus (ARC), a brain region critical to control of energy balance and glucose homeostasis, to induce these positive metabolic effects. The distribution of MasR in the ARC and their role in metabolic regulation, however, is unknown. We hypothesized: (1) MasR are expressed in the ARC; and (2) deletion of ARC MasR leads to worsened metabolic outcomes following high fat diet (HFD). To test this, male and female C57Bl/6J mice were fed a 60% HFD or matched control diet ad libitum for 12 weeks. RNAscope in situ hybridization was performed on coronal ARC sections in rostral-middle-caudal regions to determine percentage of MasR positive neurons (n=5/group). In a second experiment, we assessed body composition and insulin and glucose tolerance in transgenic mice with deletion of MasR in ARC neurons (MasR-flox with AAV5-hsyn-GFP-Cre). RNAscope revealed a wide distribution on MasR-positive cells throughout the rostral to caudal extent of the ARC. The average percentage of MasR positive neurons was increased in females versus males, with HFD tending to increase MasR expression in both sexes (control diet male: 11±2; control diet female: 17±3; HFD male: 15±5; HFD female: 24±2; p sex : 0.030; p diet : 0.066; p int : 0.615; two-way ANOVA). Deletion of MasR in ARC neurons worsened insulin sensitivity in HFD but not control diet females (area under the curve for change in glucose from baseline: -1989±1359 HFD control virus vs. 2530±1762 HFD Cre virus; p=0.016), while fasting glucose, glucose tolerance, and body composition did not change. There was no effect of ARC MasR deletion on metabolic outcomes in control diet or HFD male mice. These findings suggest females have more MasR positive neurons in the ARC compared to males, which may be a sex-specific protective mechanism for glucose homeostasis. While further studies are needed to explore the role of ARC MasR in metabolic regulation, these findings support targeting Ang-(1-7) as an innovative strategy in obesity.

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Mouse Microglial Calcitonin Receptor Knockout Impairs Hypothalamic Amylin Neuronal pSTAT3 Signaling but Lacks Major Metabolic Consequences

Metabolites ◽

10.3390/metabo12010051 ◽

2022 ◽

Vol 12 (1) ◽

pp. 51

Author(s):

Bernd Coester ◽

Thomas A. Lutz ◽

Christelle Le Foll

Keyword(s):

High Fat Diet ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Calcitonin Receptor ◽

High Fat ◽

Leptin Signaling ◽

Physiological Relevance ◽

Major Player ◽

Significant Difference ◽

Anorectic Effect

Amylin and leptin synergistically interact in the arcuate nucleus of the hypothalamus (ARC) to control energy homeostasis. Our previous rodent studies suggested that amylin-induced interleukin-6 release from hypothalamic microglia may modulate leptin signaling in agouti-related peptide expressing neurons. To confirm the physiological relevance of this finding, the calcitonin receptor (CTR) subunit of the amylin receptor was selectively depleted in microglia by crossing tamoxifen (Tx) inducible Cx3cr1-CreERT2 mice with CTR-floxed mice. Unexpectedly, male mice with CTR-depleted microglia (KO) gained the least amount of weight of all groups regardless of diet. However, after correcting for the tamoxifen effect, there was no significant difference for body weight, fat mass or lean mass between genotypes. No alteration in glucose tolerance or insulin release was detected. However, male KO mice had a reduced respiratory quotient suggesting a preference for fat as a fuel when fed a high fat diet. Importantly, amylin-induced pSTAT3 was decreased in the ARC of KO mice but this was not reflected in a reduced anorectic response. On the other hand, KO mice seemed to be less responsive to leptin’s anorectic effect while displaying similar ARC pSTAT3 as Tx-control mice. Together, these data suggest that microglial amylin signaling is not a major player in the control of energy homeostasis in mice.

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Carbonyl Reductase 1 Overexpression in Adipose Amplifies Local Glucocorticoid Action and Impairs Glucose Tolerance in Lean Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1639 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A806-A806

Author(s):

Rachel Bell ◽

Elisa Villalobos ◽

Mark Nixon ◽

Allende Miguelez-Crespo ◽

Matthew Sharp ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Tolerance ◽

Fat Mass ◽

High Fat Diet ◽

Fasting Glucose ◽

High Fat ◽

Male And Female ◽

Over Expression ◽

Female Mice ◽

Diet Induced Obesity

Abstract Glucocorticoids play a critical role in metabolic homeostasis. Chronic or excessive activation of the glucocorticoid receptor (GR) in adipose tissue contributes to metabolic disorders such as glucose intolerance and insulin resistance. Steroid-metabolising enzymes in adipose, such as 11β-HSD1 or 5α-reductase, modulate the activation of GR by converting primary glucocorticoids into more or less potent ligands. Carbonyl reductase 1 (CBR1) is a novel regulator of glucocorticoid metabolism, converting corticosterone/cortisol to 20β-dihydrocorticosterone/cortisol (20β-DHB/F); a metabolite which retains GR activity. CBR1 is abundant in adipose tissue and increased in obese adipose of mice and humans1 and increased Cbr1 expression is associated with increased fasting glucose1. We hypothesised that increased Cbr1/20β-DHB in obese adipose contributes to excessive GR activation and worsens glucose tolerance. We generated a novel murine model of adipose-specific Cbr1 over-expression (R26-Cbr1Adpq) by crossing conditional knock-in mice with Adiponectin-Cre mice. CBR1 protein and activity were doubled in subcutaneous adipose tissue of male and female R26-Cbr1Adpq mice compared with floxed controls; corresponding to a two-fold increase 20β-DHB (1.6 vs. 4.2ng/g adipose; P=0.0003; n=5-7/group). There were no differences in plasma 20β-DHB or corticosterone. Bodyweight, lean or fat mass, did not differ between male or female R26-Cbr1Adpq mice and floxed controls. Lean male R26-Cbr1Adpq mice had higher fasting glucose (9.5±0.3 vs. 8.4±0.3mmol/L; P=0.04) and worsened glucose tolerance (AUC 1819±66 vs. 1392±14; P=0.03). Female R26-Cbr1Adpq mice also had a worsened glucose tolerance but fasting glucose was not altered with genotype. There were no differences in fasting insulin or non-esterified fatty acid between genotypes in either sex. Expression of GR-induced genes Pnpla2, Gilz and Per1, were increased in adipose of R26-Cbr1Adpq mice. Following high-fat diet induced obesity, no differences in bodyweight, lean or fat mass, with genotype were observed in male and female mice, and genotype differences in fasting glucose and glucose tolerance were abolished. In conclusion, adipose-specific over-expression of Cbr1 in lean male and female mice led to increased levels of 20β-DHB in adipose but not plasma, and both sexes having worsened glucose tolerance. The influence of adipose CBR1/20β-DHB on glucose tolerance was not associated with altered fat mass or bodyweight and was attenuated by high-fat diet-induced obesity. These metabolic consequences of Cbr1 manipulation require careful consideration given the wide variation in CBR1 expression in the human population, the presence of inhibitors and enhancers in many foodstuffs and the proposed use of inhibitors as an adjunct for cancer treatment regimens. Reference: Morgan et al., Scientific Reports. 2017; 7.

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