Mechanistic role of antioxidants in rescuing delayed gastric emptying in high fat diet induced diabetic female mice

Abstract Risk factors for non-alcoholic hepatic steatosis include obesity and vitamin D deficiency which commonly co-exist. Thus, the role of vitamin D signaling in the prevention of hepatic steatosis in the absence of obesity or a “western” high fat diet is unclear. These studies were performed to address the role of the adipocyte Vitamin D Receptor (VDR) in the prevention of hepatic steatosis in mice fed a chow diet containing 5% fat by weight. Female mice with adipocyte VDR ablation (Adipoq-Cre; VDR flox/flox) exhibited a mild increase in weight gain at 70 days of age, accompanied by an increase in visceral adipose tissue (VAT) weight. While they did not exhibit evidence of hepatic inflammation or fibrosis, an increase in hepatic lipid content was observed. This was accompanied by an increase in the hepatic expression of genes involved in fatty acid transport and synthesis, as well as fatty acid oxidation. Markers of hepatic inflammation and fibrosis were unaffected by adipocyte VDR ablation. Consistent with the increase in VAT weight in the Adipoq-Cre; VDR flox/flox mice, higher levels of transcripts encoding adiopogenesis related genes were observed in VAT. In contrast to other models of impaired vitamin D signaling studied in the setting of a high fat or “western” diet, the Adipoq-Cre; VDR flox/flox mice do not exhibit hepatic inflammation or fibrosis. These findings suggest that the adipocyte VDR regulates hepatic lipid accumulation, but in the absence of obesity or a high fat diet, is not required to prevent hepatic inflammation or fibrosis.

Download Full-text

The role of endocannabinoids in the regulation of gastric emptying: alterations in mice fed a high-fat diet

British Journal of Pharmacology ◽

10.1038/sj.bjp.0707682 ◽

2008 ◽

Vol 153 (6) ◽

pp. 1272-1280 ◽

Cited By ~ 74

Author(s):

V Di Marzo ◽

R Capasso ◽

I Matias ◽

G Aviello ◽

S Petrosino ◽

...

Keyword(s):

Gastric Emptying ◽

High Fat Diet ◽

High Fat

Download Full-text

OR12-06 Nuclear Receptor CAR Protects Female Mice from the Development of Diet-Induced Nonalcoholic Fatty Liver Disease

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1888 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Fabiana Layla Oliviero ◽

Céline Lukowicz ◽

Lucile Mary ◽

Laila Lakhal

Keyword(s):

Liver Disease ◽

Hepatic Steatosis ◽

Nuclear Receptor ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Sexually Dimorphic ◽

High Fat ◽

Knock Out ◽

Female Mice

Abstract NAFLD (Non Alcoholic Fatty Liver Disease) has become the most common cause of chronic liver disease in many developed countries worldwide and represents a major health concern. The prevalence of NAFLD is sexually dimorphic with men suspected to be more susceptible to the development of hepatic steatosis than women. Women are mostly protected until hormonal imbalance induced by menopause. Nuclear receptor CAR (Constitutive Androstan Receptor) is at the crossroads between endocrine and metabolic regulations and could therefore represent an interesting therapeutic target. It is primarily expressed in the liver and involved in the catabolism of hormones such as thyroid hormones, corticosteroids and estrogens. In addition, several studies reveal a metabolic role of CAR through regulation of major hepatic pathways such as neoglucogenesis, beta-oxidation and de novo lipogenesis. Our research is aimed at better understanding the role of CAR using a mouse model genetically deficient for CAR. To explore the metabolic functions of CAR, knock-out male and female mice were subjected to a high fat diet (HFD) for 16 weeks. Concomitant CAR deletion and high fat diet induces sexually dimorphic metabolic disorders. Knock-out of CAR in males exacerbates HFD-induced fasted hyperglycemia whereas in females, it aggravates body weight gain and adipose tissue accumulation. In accordance with epidemiological studies revealing a protection of women from the development of hepatic steatosis, HFD-fed WT female mice present less important hepatic steatosis than HFD-fed WT male mice. However, following CAR deletion, HFD-fed female mice develop a severe steatosis along with important hepatic injury. Ongoing studies aim to understand the transcriptomic and endocrine dysregulations that may explain these phenotypes. These results reveal a previously unrecognized dimorphic role of CAR in energy homeostasis and highlights its involvement in the protection of female mice towards the development of hepatic steatosis. Overall, this research provides further insights in the pathogenesis of NAFLD and its dimorphic prevalence.

Download Full-text

Upregulation of bile acid receptor TGR5 and nNOS in gastric myenteric plexus is responsible for delayed gastric emptying after chronic high-fat feeding in rats

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00380.2014 ◽

2015 ◽

Vol 308 (10) ◽

pp. G863-G873 ◽

Cited By ~ 7

Author(s):

Hui Zhou ◽

Shiyi Zhou ◽

Jun Gao ◽

Guanpo Zhang ◽

Yuanxu Lu ◽

...

Keyword(s):

Bile Acid ◽

Gastric Emptying ◽

Myenteric Plexus ◽

High Fat Diet ◽

Delayed Gastric Emptying ◽

High Fat ◽

Bile Acid Receptor ◽

Fat Feeding ◽

Nanc Relaxation ◽

Nnos Expression

Chronic high-fat feeding is associated with functional dyspepsia and delayed gastric emptying. We hypothesize that high-fat feeding upregulates gastric neuronal nitric oxide synthase (nNOS) expression, resulting in delayed gastric emptying. We propose this is mediated by increased bile acid action on bile acid receptor 1 (TGR5) located on nNOS gastric neurons. To test this hypothesis, rats were fed regular chow or a high-fat diet for 2 wk. Rats fed the high-fat diet were subjected to concurrent feeding with oral cholestyramine or terminal ileum resection. TGR5 and nNOS expression in gastric tissue was measured by immunohistochemistry, PCR, and Western blot. Gastric motility was assessed by organ bath and solid-phase gastric emptying studies. The 2-wk high-fat diet caused a significant increase in neurons coexpressing nNOS and TGR5 in the gastric myenteric plexus and an increase in nNOS and TGR5 gene expression, 67 and 111%, respectively. Enhanced nonadrenergic, noncholinergic (NANC) relaxation, deoxycholic acid (DCA)-induced inhibition in fundic tissue, and a 26% delay in gastric emptying accompanied these changes. A 24-h incubation of whole-mount gastric fundus with DCA resulted in increased nNOS and TGR5 protein expression, 41 and 37%, respectively. Oral cholestyramine and terminal ileum resection restored the enhanced gastric relaxation, as well as the elevated nNOS and TGR5 expression evoked by high-fat feeding. Cholestyramine also prevented the delay in gastric emptying. We conclude that increased levels of circulatory bile acids induced by high-fat feeding upregulate nNOS and TGR5 expression in the gastric myenteric plexus, resulting in enhanced NANC relaxation and delayed gastric emptying.

Download Full-text

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00287.2017 ◽

2018 ◽

Vol 314 (3) ◽

pp. R478-R488 ◽

Cited By ~ 7

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.

Download Full-text