Deletion of PTP 1B from Brain Neurons Partly Protects Mice from Diet-Induced Obesity and Minimally Improves Fertility

Endocrinology ◽  
2021 ◽  
Author(s):  
Caroline M Ancel ◽  
Maggie C Evans ◽  
Romy I Kerbus ◽  
Elliot G Wallace ◽  
Greg M Anderson
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Glucose Tolerance ◽  
Knockout Mice ◽  
Body Weight Gain ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Male And Female ◽  
Female Mice ◽  
Calorie Diet

Abstract Reproductive dysfunction in women has been linked to high calorie diet (HCD)-feeding and obesity. Central resistance to leptin and insulin have been shown to accompany diet-induced infertility in rodent studies, and we have previously shown that deleting suppressor of cytokine signaling 3, which is a negative regulator of leptin signaling, from all forebrain neurons partially protects mice from HCD-induced infertility. In this study, we were interested in exploring the role of protein tyrosine phosphatase 1B (PTP1B), which is a negative regulator of both leptin and insulin signaling, in the pathophysiology of HCD-induced obesity and infertility. To this end, we generated male and female neuron-specific PTP1B knockout mice and compared their body weight gain, food intake, glucose tolerance and fertility to control littermates under both normal calorie diet-feeding and HCD-feeding conditions. Both male and female mice with neuronal PTP1B deletion exhibited slower body weight gain in response to HCD-feeding, yet only male knockout mice exhibited improved glucose tolerance compared with controls. Neuronal PTP1B deletion improved the time to first litter in HCD-fed mice, but did not protect female mice from eventual HCD-induced infertility. While the mice fed a normal caloric diet remained fertile throughout the 150 day period of assessment, HCD-fed females became infertile after producing only a single litter, regardless of their genotype. These data show that neuronal PTP1B deletion is able to partially protect mice from HCD-induced obesity, but is not a critical mediator of HCD-induced infertility.

scholarly journals Tpcn2 knockout mice have improved insulin sensitivity and are protected against high-fat diet-induced weight gain

2018 ◽  
Vol 50 (8) ◽  
pp. 605-614
Author(s):  
Hong He ◽  
Katie Holl ◽  
Sarah DeBehnke ◽  
Chay Teng Yeo ◽  
Polly Hansen ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Male And Female ◽  
Female Mice

Type 2 diabetes is a complex disorder affected by multiple genes and the environment. Our laboratory has shown that in response to a glucose challenge, two-pore channel 2 ( Tpcn2) knockout mice exhibit a decreased insulin response but normal glucose clearance, suggesting they have improved insulin sensitivity compared with wild-type mice. We tested the hypothesis that improved insulin sensitivity in Tpcn2 knockout mice would protect against the negative effects of a high fat diet. Male and female Tpcn2 knockout (KO), heterozygous (Het), and wild-type (WT) mice were fed a low-fat (LF) or high-fat (HF) diet for 24 wk. HF diet significantly increases body weight in WT mice relative to those on the LF diet; this HF diet-induced increase in body weight is blunted in the Het and KO mice. Despite the protection against diet-induced weight gain, however, Tpcn2 KO mice are not protected against HF-diet-induced changes in glucose or insulin area under the curve during glucose tolerance tests in female mice, while HF diet has no significant effect on glucose tolerance in the male mice, regardless of genotype. Glucose disappearance during an insulin tolerance test is augmented in male KO mice, consistent with our previous findings suggesting enhanced insulin sensitivity in these mice. Male KO mice exhibit increased fasting plasma total cholesterol and triglyceride concentrations relative to WT mice on the LF diet, but this difference disappears in HF diet-fed mice where there is increased cholesterol and triglycerides across all genotypes. These data demonstrate that knockout of Tpcn2 may increase insulin action in male, but not female, mice. In addition, both male and female KO mice are protected against diet-induced weight gain, but this protection is likely independent from glucose tolerance, insulin sensitivity, and plasma lipid levels.

Abstract 077: Role of Suppressor of Cytokines Signaling 3 (SOCS3) in POMC Neurons in Regulating Metabolic and Cardiovascular Functions in Dietary-Induced Obesity

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Zhen Wang ◽  
Jussara do Carmo ◽  
Alexandre da Silva ◽  
Nicola Aberdein ◽  
John Hall
Keyword(s):  
Food Intake ◽  
Glucose Tolerance ◽  
Body Weight Gain ◽  
Negative Regulator ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
Male And Female ◽  
Air Jet ◽  
Cardiovascular Functions

Suppressor of cytokine signaling 3 (SOCS3), a negative regulator of leptin signaling, may contribute to the development of obesity-induced leptin resistance. Previously, we showed that activation of proopiomelanocortin (POMC) neurons mediates the chronic effects of leptin on blood pressure (BP) and glucose regulation. However, the role of SOCS3 in POMC neurons in regulating metabolic and cardiovascular functions in obesity is still unclear. To address this question, we used male and female mice with SOCS3 deleted only in POMC neurons (SOCS3 flox/flox -POMC/cre) and flox control (SOCS3 flox/flox ) mice. After weaning, mice were fed normal chow until 20 wks of age; then glucose tolerance tests (GTT) were performed and telemetry probes were implanted to measure mean arterial pressure (MAP) 24-hrs/day. We found that at 23 wks of age, both male and female SOCS3 flox/flox -POMC/cre mice weighed less than control mice (32±1 vs 37±2 g in male and 25±1 vs 27±1 g in female, n=9-11, p <0.05), but had similar daily food intake (3.5±0.2 g in male and 3.3±0.1 g in female) and MAP (114±1 vs 115±2 mmHg). Only male SOCS3 flox/flox -POMC/cre mice exhibited improved glucose tolerance (AUC: 1059±52 vs 1283±54 mg/dL x 120 min, n=7-10, p <0.05) compared to controls. From 23 wks, mice were switched to a high fat diet (45%, HFD) for 6 wks. After HFD feeding, both male and female SOCS3 flox/flox -POMC/cre mice had slightly reduced food intake (3.2±0.1 vs 3.5±0.2 g in male and 2.7±0.1 vs 3.0±0.2 g in female) and a trend toward lower body weight gain (10±1 vs 12±1 g in male and 4±1 vs 6±1 g in female), although the differences were not significant compared to controls. However, male and female SOCS3 flox/flox -POMC/cre mice fed a HFD had significantly greater MAP increase (7±1 vs 1±1 mmHg, n=13-16, p <0.05) and an enhanced BP response to acute air-jet stress (AUC: 109±9 vs 74±12 mmHg x 5min, n=8-13, p <0.05). After HFD, glucose tolerance was impaired in all groups of mice compared to the baseline at 20 wks, but there were no differences between SOCS3 flox/flox -POMC/cre and controls. These results suggest that deletion of SOCS3 in POMC neurons amplifies the BP response to a HFD and to acute stress, but has minimal effects on metabolic functions to HFD. (NHLBI PO1HL51971, NIGMS P20GM104357, AHA 14POST18160019)

scholarly journals Sex and Genotype Dependent Effects of a Restricted Access Diet in Ghrelin-Deficient Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A56-A56
Author(s):  
Karina Prins ◽  
Patric J Delhanty ◽  
Martin Huisman ◽  
Rosinda Mies ◽  
Anke McLuskey ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Locomotor Activity ◽  
Food Intake ◽  
Energy Expenditure ◽  
Glucose Tolerance ◽  
Body Weight Gain ◽  
Light Phase ◽  
Male And Female ◽  
Restricted Access

Abstract Ghrelin, a peptide hormone secreted by the stomach, stimulates both appetite and reward signalling. Its deletion in mice results in poor recovery from metabolic challenges, like starvation, but does not affect food intake or body weight. While sex differences in appetite and feeding behavior have been reported, little is known about the role of ghrelin herein. To investigate this, we used a metabolic cage system to continuously monitor responses of ghrelin-deficient (GKO) and wildtype (WT) mice to three different diets. Male and female mice (5 weeks old) were housed individually in a Promethion system (Sable Systems, USA) and provided one of three diets for 9 weeks: RA, continuous chow with restricted access to a Western-style diet (WD; 2h access, 3d/week) in the light phase; CA, continuous access to both diets; CC, continuous chow. Glucose tolerance was assessed at week 7 by IPGTT; food intake (kcal/g bodyweight), energy expenditure and locomotor activity at week 8; body weight and body composition (EchoMRI, USA) at week 9. On access days, RA mice ate up to 60% of their 24h intake during the WD access period. Following WD access GKO RA mice ate less chow than WT RA mice. Intriguingly, this compensatory reduction in food intake by GKO mice occurred at different times for males and females. GKO RA males ate 45% less chow in the dark phase immediately after WD access (p &lt; 0.001). In contrast, this reduction in food intake (30% less) did not occur until the following, non-access, day in GKO RA females (genotype-sex: p &lt; 0.05). Depending on diet, GKO mice showed differential regulation of energy expenditure in the light phase. Energy expenditure was 6–17% higher in GKO than WT mice in the RA group on access days and in the CA group. On non-access days, however, GKO mice in the RA group expended 13% less energy than WT RA mice (p &lt; 0.005). Regardless of diet, locomotor activity in females was greater than in males (p &lt; 0.001). However, GKO females in the RA and CC groups showed a marked 30% reduction in locomotor activity compared to WTs (genotype-sex: p &lt; 0.05). After nine weeks, neither sex nor genotype effects were seen in body weight gain and composition of RA animals. CA females gained 17% more body weight and had a 6.1% higher fat percentage than CA males (both p &lt; 0.001). In the CC group body weight gain did not differ, but GKO females had 3.1% more fat than WT females (genotype-sex: p &lt; 0.01). Glucose tolerance (AUC) was similar in all groups. In conclusion, we demonstrated that ghrelin deficiency changes the response to the three diets in a sex-dependent manner. Especially, restricted access to WD differentially affected food intake timing and locomotor activity of male and female GKO mice. These results add to the growing body of evidence that ghrelin signalling is sexually dimorphic.

Abstract P076: Suppressor of Cytokine Signaling 3 (SOCS3) in POMC Neurons and Its Role in Regulating Blood Pressure, Body Weight and Glucose in Obesity

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Zhen Wang ◽  
Jussara M do Carmo ◽  
Alexandre A da Silva ◽  
John E Hall
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Food Intake ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Male And Female ◽  
Female Mice ◽  
And Control

Suppressor of cytokine signaling 3 (SOCS3), a negative regulator of leptin signaling, may be involved in development of obesity-induced leptin resistance. Although we previously showed that activation of proopiomelanocortin (POMC) neurons mediates the chronic effects of leptin on blood pressure (BP), the role of SOCS3 in modulating BP in obesity is still unclear. In this study, we investigated the role of SOCS3 specifically in POMC neurons in regulating body weight, glucose handling and BP in mice fed a normal or high fat (45%, HFD) chow. Male and female SOCS3flox/flox-POMC/cre mice in which SOCS3 was selectively deleted in POMC neurons and control SOCS3flox/flox mice were used. Food intake and body weight were measured from 8 to 16 weeks of age, and a glucose tolerance test (GTT) was performed at 20 wks of age. At 22 wks of age, mice were implanted with telemetry probe to measure BP and heart rate (HR) and fed a HFD for 6 weeks. Compared to control mice, both male and female SOCS3flox/flox-POMC/cre mice were lighter at 16 wks (29.1 ± 3.5 vs 31.9 ± 3.6 g in male and 21.5 ± 2.2 vs 26.1 ± 5.7 in female, n=9-11, p<0.05) but food intake was similar in both groups. Only male SOCS3flox/flox-POMC/cre mice exhibited improved glucose handling (AUC: 1059 ± 52 vs 1283 ± 54 mg/dL x 120 min, n=7-10, p<0.05 ) and no differences were observed in female mice. When fed normal chow, BP was similar in SOCS3flox/flox-POMC/cre and control mice (116 ± 7 vs 113 ± 5 mmHg) at 23 wks. After a HFD for 6 weeks, SOCS3flox/flox-POMC/cre mice had a greater BP increase compared to control mice (7.2 ± 1.9 vs 0.9 ± 1.8 mmHg, n=4-9, P<0.05) but no significant differences were observed in food intake or body weight between two groups. These results suggest that SOCS3 deletion specifically in POMC neurons reduced body weight in male and female mice, and improved glucose handling only in male mice. HFD increased BP in SOCS3flox/flox-POMC/cre but not in control mice, suggesting that SOCS3 in POMC neurons may modulate BP response to HFD.

scholarly journals Role of PTP1B in POMC neurons during chronic high-fat diet: sex differences in regulation of liver lipids and glucose tolerance

2018 ◽  
Vol 314 (3) ◽  
pp. R478-R488 ◽  
Author(s):  
Nicola Aberdein ◽  
Robert J. Dambrino ◽  
Jussara M. do Carmo ◽  
Zhen Wang ◽  
Laura E. Mitchell ◽  
...  
Keyword(s):  
Sex Differences ◽  
Weight Gain ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Acute Stress ◽  
Negative Regulator ◽  
High Fat ◽  
Male And Female ◽  
Female Mice

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of leptin receptor signaling and may contribute to leptin resistance in diet-induced obesity. Although PTP1B inhibition has been suggested as a potential weight loss therapy, the role of specific neuronal PTP1B signaling in cardiovascular and metabolic regulation and the importance of sex differences in this regulation are still unclear. In this study, we investigated the impact of proopiomelanocortin (POMC) neuronal PTP1B deficiency in cardiometabolic regulation in male and female mice fed a high-fat diet (HFD). When compared with control mice (PTP1B flox/flox), male and female mice deficient in POMC neuronal PTP1B (PTP1B flox/flox/POMC-Cre) had attenuated body weight gain (males: −18%; females: −16%) and fat mass (males: −33%; female: −29%) in response to HFD. Glucose tolerance was improved by 40%, and liver lipid accumulation was reduced by 40% in PTP1B/POMC-Cre males but not in females. When compared with control mice, deficiency of POMC neuronal PTP1B did not alter mean arterial pressure (MAP) in male or female mice (males: 112 ± 1 vs. 112 ± 1 mmHg in controls; females: 106 ± 3 vs. 109 ± 3 mmHg in controls). Deficiency of POMC neuronal PTP1B also did not alter MAP response to acute stress in males or females compared with control mice (males: Δ32 ± 0 vs. Δ29 ± 4 mmHg; females: Δ22 ± 2 vs. Δ27 ± 4 mmHg). These data demonstrate that POMC-specific PTP1B deficiency improved glucose tolerance and attenuated diet-induced fatty liver only in male mice and attenuated weight gain in males and females but did not enhance the MAP and HR responses to a HFD or to acute stress.

scholarly journals Effects of Bisphenol-A (BPA) and black seed oil on body weight, lipid profile and serum glucose in male and female mice

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
K. M. Sujan ◽  
E. Haque ◽  
M. S. Rakib ◽  
M. I. Haque ◽  
A. Mustari ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Bisphenol A ◽  
Lipid Profile ◽  
Seed Oil ◽  
Serum Glucose ◽  
Male And Female ◽  
Female Mice ◽  
Black Seed ◽  
Black Seed Oil

Background: Bisphenol-A [BPA, 2, 2-bis (hydroxyphenyl) propane] is widely used in the manufacture of polycarbonate plastic, water bottles, feeders , baby bottles, epoxy resins and inside coating in metallic food cans. Black seed oil (BSO) (Nigella sativa) commonly known as black cumin, reported to be beneficial in function of various systems in the body. The study was carried out to investigate the effect of BPA and BSO on body weight, lipid profile and serum glucose in male and female mice. Methods : A total of thirty (15 male and 15 female) Swiss Albino mice (Mus musculus), aged 25-28 days with an average body weight of 27.4±1g were randomly divided into 3 groups consisting 5 mice in each for each sex. Group A served as vehicle control. Group B was administered BPA @ 50 mg/kg bw daily, while group C received both BPA @ 50 mg/kg/day and BSO @ 1ml/kg/day respectively. Results: Data revealed that BPA treated mice showed slight increase in body weight gain while BSO controlled the weight gain in BPA treated mice. Cholesterol and LDL values were significantly (p<0.01) increased and Triglycerides value was significantly (p<0.01) decreased in BPA-treated mice without significant alterations in HDL value. BPA & BSO treated female mice showed significant (p<0.01) decreased in cholesterol, triglycerides and LDL values. BPA reduced the blood glucose level and addition of BSO had synergistic effects of glucose utilization. Conclusions: It can be concluded that BPA is one of the potential risk factors for hyperlipidemia and obesity. These harmful effects could be alleviated by the ingestion of black seed oil.

scholarly journals Role of SOCS3 in POMC neurons in metabolic and cardiovascular regulation

2019 ◽  
Vol 316 (4) ◽  
pp. R338-R351 ◽  
Author(s):  
Zhen Wang ◽  
Jussara M. do Carmo ◽  
Alexandre A. da Silva ◽  
Kandice C. Bailey ◽  
Nicola Aberdein ◽  
...  
Keyword(s):  
Heart Rate ◽  
Body Weight ◽  
Food Intake ◽  
Stress Test ◽  
Control Diet ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Male And Female ◽  
Air Jet ◽  
And Control

Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of leptin signaling. We previously showed that the chronic effects of leptin on blood pressure (BP) and glucose regulation are mediated by stimulation of proopiomelanocortin (POMC) neurons. In this study we examined the importance of endogenous SOCS3 in POMC neurons in control of metabolic and cardiovascular function and potential sex differences. Male and female SOCS3flox/flox/POMC-Cre mice in which SOCS3 was selectively deleted in POMC neurons and control SOCS3flox/flox mice were studied during a control diet (CD) or a high-fat diet (HFD) and during chronic leptin infusion. Body weight was lower in male and female SOCS3flox/flox/POMC-Cre than control mice fed the CD, despite similar food intake. Male SOCS3flox/flox/POMC-Cre mice exhibited increased energy expenditure. BP and heart rate were similar in male and female SOCS3flox/flox/POMC-Cre and control mice fed the CD. HFD-fed male and female SOCS3flox/flox/POMC-Cre mice showed attenuated weight gain. HFD-induced elevations in baseline BP and BP responses to an air-jet stress test were greater in female SOCS3flox/flox/POMC-Cre than control mice. Chronic leptin infusion produced similar responses for food intake, body weight, oxygen consumption, blood glucose, BP, and heart rate in all groups. Thus SOCS3 deficiency in POMC neurons influences body weight regulation in the setting of CD and HFD and differentially affects BP and energy balance in a sex-specific manner but does not amplify the dietary, glycemic, or cardiovascular effects of leptin.

scholarly journals Effect of chronic infusion of olanzapine and clozapine on food intake and body weight gain in male and female rats

Life Sciences ◽  
2007 ◽  
Vol 81 (12) ◽  
pp. 1024-1030 ◽  
Author(s):  
SuJean Choi ◽  
Briana DiSilvio ◽  
JayLynn Unangst ◽  
John D. Fernstrom
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Food Intake ◽  
Body Weight Gain ◽  
Female Rats ◽  
Male And Female ◽  
Male And Female Rats ◽  
Chronic Infusion

Chronic benzylamine administration in the drinking water improves glucose tolerance, reduces body weight gain and circulating cholesterol in high-fat diet-fed mice

2010 ◽  
Vol 61 (4) ◽  
pp. 355-363 ◽  
Author(s):  
Zsuzsa Iffiú-Soltész ◽  
Estelle Wanecq ◽  
Almudena Lomba ◽  
Maria P. Portillo ◽  
Federica Pellati ◽  
...  
Keyword(s):  
Drinking Water ◽  
Body Weight ◽  
Weight Gain ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Body Weight Gain ◽  
High Fat

scholarly journals Deficiency of FcϵR1 Increases Body Weight Gain but Improves Glucose Tolerance in Diet-Induced Obese Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4047-4058 ◽  
Author(s):  
Yun-Jung Lee ◽  
Conglin Liu ◽  
Mengyang Liao ◽  
Galina K. Sukhova ◽  
Jun Shirakawa ◽  
...  
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Insulin Secretion ◽  
Weight Gain ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Body Weight Gain ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Enhancer Binding Protein

Prior studies demonstrated increased plasma IgE in diabetic patients, but the direct participation of IgE in diabetes or obesity remains unknown. This study found that plasma IgE levels correlated inversely with body weight, body mass index, and body fat mass among a population of randomly selected obese women. IgE receptor FcϵR1-deficient (Fcer1a−/−) mice and diet-induced obesity (DIO) mice demonstrated that FcϵR1 deficiency in DIO mice increased food intake, reduced energy expenditure, and increased body weight gain but improved glucose tolerance and glucose-induced insulin secretion. White adipose tissue from Fcer1a−/− mice showed an increased expression of phospho-AKT, CCAAT/enhancer binding protein-α, peroxisome proliferator-activated receptor-γ, glucose transporter-4 (Glut4), and B-cell lymphoma 2 (Bcl2) but reduced uncoupling protein 1 (UCP1) and phosphorylated c-Jun N-terminal kinase (JNK) expression, tissue macrophage accumulation, and apoptosis, suggesting that IgE reduces adipogenesis and glucose uptake but induces energy expenditure, adipocyte apoptosis, and white adipose tissue inflammation. In 3T3-L1 cells, IgE inhibited the expression of CCAAT/enhancer binding protein-α and peroxisome proliferator-activated receptor-γ, and preadipocyte adipogenesis and induced adipocyte apoptosis. IgE reduced the 3T3-L1 cell expression of Glut4, phospho-AKT, and glucose uptake, which concurred with improved glucose tolerance in Fcer1a−/− mice. This study established two novel pathways of IgE in reducing body weight gain in DIO mice by suppressing adipogenesis and inducing adipocyte apoptosis while worsening glucose tolerance by reducing Glut4 expression, glucose uptake, and insulin secretion.

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