Abstract 022: mTORC1 is Required for the Cardiovascular but Not the Metabolic Actions of Leptin

Obesity represents a major risk factor for the development of hypertension, and inappropriate leptin action has been implicated as an essential mediator of obesity-associated hypertension. Leptin plays a critical role in energy homeostasis, acting through the brain to stimulate energy expenditure and suppress food intake. Leptin also increases sympathetic outflow to a variety of target organs, including those involved in blood pressure regulation. Here, we investigate the role of mTORC1 as a potential mediator of leptin’s cardiovascular and metabolic actions. For this, we generated conditional knockout mice that lack the critical mTORC1 subunit, Raptor, specifically in leptin receptor (LRb) expressing cells (LRb Cre /Rap fl/fl ). LRb Cre /Rap fl/fl displayed similar body weight, food intake and body composition as compared to littermate controls when fed a normal chow diet (body weight=29.6±0.8 g vs 31.0±0.8g at 14 weeks of age). Control and LRb Cre /Rap fl/fl mice also developed diet-induced obesity to a similar extent when fed either a 45% high-fat (37.2±3.1g g vs 40.9±2.2) or high-fat/high-sucrose diet (35.4±1.1g vs 35.2±2.7g). Additionally, fasting blood glucose (77.3±6.7mg/dL vs. 71.8±4.3mg/dL) as well as insulin (AUC=7788 ±1013, n=3 vs. 8964±884, n=4) and glucose (AUC=39750±2075, n=3 vs. 44259±1948, n=4) tolerance in high fat/high-sucrose diet fed mice were not changed in LRb Cre /Rap fl/fl mice as compared to littermate controls. Conversely, while baseline mean arterial pressure (MAP) was comparable between LRb Cre /Rap fl/fl mice (108±9 mmHg) and controls (103±7 mmHg), intracerebroventricular administration of leptin significantly increased MAP in control mice (30±14 mmHg), but not in LRb Cre /Rap fl/fl mice (1±9 mmHg, P<0.05 vs controls). Consistent with this, LRb Cre /Rap fl/fl mice displayed a blunted renal sympathetic nerve response to leptin (-4±15%, n=9 vs. 127±16%, n=9, P<0.05) but a preserved increase in sympathetic outflow to brown adipose tissue (109±27%, n=5 vs. 173±52%, n=4). Together, our data indicate a critical role for mTORC1 in mediating the cardiovascular but not the metabolic effects of leptin.

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Ghrelin O-acyltransferase knockout mice show resistance to obesity when fed high-sucrose diet

Journal of Endocrinology ◽

10.1530/joe-15-0330 ◽

2015 ◽

Vol 228 (2) ◽

pp. 115-125 ◽

Cited By ~ 19

Author(s):

Tetsuya Kouno ◽

Nobuteru Akiyama ◽

Takahito Ito ◽

Tomohiko Okuda ◽

Isamu Nanchi ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Glucose Metabolism ◽

High Fat Diet ◽

Acylated Ghrelin ◽

High Fat ◽

Obesity And Diabetes ◽

Sucrose Diet ◽

High Sucrose Diet ◽

High Sucrose

Ghrelin is an appetite-stimulating hormone secreted from stomach. Since the discovery that acylation of the serine-3 residue by ghrelin O-acyltransferase (GOAT) is essential for exerting its functions, GOAT has been regarded as an therapeutic target for attenuating appetite, and thus for the treatment of obesity and diabetes. However, contrary to the expectations, GOAT-knockout (KO) mice have not shown meaningful body weight reduction, under high-fat diet. Here, in this study, we sought to determine whether GOAT has a role in body weight regulation and glucose metabolism with a focus on dietary sucrose, because macronutrient composition of diet is important for appetite regulation. We found that peripherally administered acylated-ghrelin, but not unacylated one, stimulated sucrose consumption in a two-bottle-drinking test. The role of acylated-ghrelin in sucrose preference was further supported by the finding that GOAT KO mice consumed less sucrose solution compared with WT littermates. Then, we investigated the effect of dietary composition of sucrose on food intake and body weight in GOAT KO and WT mice. As a result, when fed on high-fat diet, food intake and body weight were similar between GOAT KO and WT mice. However, when fed on high-fat, high-sucrose diet, GOAT KO mice showed significantly reduced food intake and marked resistance to obesity, leading to amelioration of glucose metabolism. These results suggest that blockade of acylated-ghrelin production offers therapeutic potential for obesity and metabolic disorders caused by overeating of palatable food.

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Influence of Saskatoon Berry and Cyanidin-3-Glucoside on Gut Microbiota and Relationship with Metabolism and Inflammation in High Fat-High Sucrose Diet-Induced Insulin Resistant Mice

10.21203/rs.3.rs-36586/v1 ◽

2020 ◽

Author(s):

Fei Huang ◽

Ruozhi Zhao ◽

Mi Xia ◽

Garry Shen

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Gut Microbiota ◽

Inflammatory Mediators ◽

Inflammatory Markers ◽

High Fat ◽

Insulin Resistant ◽

Sucrose Diet ◽

High Sucrose Diet ◽

High Sucrose

Abstract Background Type 2 Diabetes (T2D) has become one of most common and harmful chronic diseases worldwide. T2D is characterized as insulin resistant and is often associated with unhealthy dietary habits. The present study assessed the effects of freeze-dried Saskatoon berry powder (SBp) and cyanidin-3-glucoside (C3G, an anthocyanin enriched in SBp) on metabolism, inflammatory markers and gut microbiota in high fat-high sucrose diet (HFHS) diet induced insulin resistant mice. Results Male C57 BL/6J mice received control, HFHS, HFHS + SBp (8.0 g/kg body weight/day) or HFHS + C3G (7.2 mg/kg/day, equal amount of C3G in 8.0 g/kg/day SBp) diet for 11 weeks. HFHS diet significantly increased the levels of glucose, cholesterol, triglycerides, insulin resistance and inflammatory mediators in plasma. The results of 16S rRNA gene sequencing demonstrated that HFHS diet increased the ratio of Bacteroidetes/Firmicutes (B/F) phylum bacteria and an elevated abundance of Muriculaceae family bacteria in the feces of mice. SBp or C3G supplementation attenuated HFHS diet-induced disorders in metabolism and inflammatory markers, and increased B/F ratio and Muriculaceae abundance in mouse gut compared to HFHS diet alone. The abundance of Muriculaceae in the gut microbiota negatively correlated with body weight, glucose, lipids, insulin resistance and inflammatory mediators in mice. The results of functional predication analysis suggest that HFHS diet upregulated the genes of gut bacteria involved in inflammation-related cellular processes, and inhibited bacteria involved in metabolism. SBp and C3G partially neutralized the alterations induced by HFHS diet in gut microbiota implicated in metabolism or inflammation. Conclusion The findings of the present study suggest that SBp is a potential prebiotic food mitigating Western diet-induced disorders in metabolism, inflammation and gut dysbiosis, and C3G possibly contributes to the beneficial effects of SBp.

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Polymannuronic acid ameliorated obesity and inflammation associated with a high-fat and high-sucrose diet by modulating the gut microbiome in a murine model

British Journal Of Nutrition ◽

10.1017/s0007114517000964 ◽

2017 ◽

Vol 117 (9) ◽

pp. 1332-1342 ◽

Cited By ~ 22

Author(s):

Fang Liu ◽

Xiong Wang ◽

Hongjie Shi ◽

Yuming Wang ◽

Changhu Xue ◽

...

Keyword(s):

Body Weight ◽

Weight Gain ◽

Gut Microbiome ◽

Body Weight Gain ◽

High Fat ◽

Microbial Composition ◽

The Metabolic Syndrome ◽

Sucrose Diet ◽

High Sucrose Diet ◽

High Sucrose

AbstractPolymannuronic acid (PM), one of numerous alginates isolated from brown seaweeds, is known to possess antioxidant activities. In this study, we examined its potential role in reducing body weight gain and attenuating inflammation induced by a high-fat and high-sucrose diet (HFD) as well as its effect on modulating the gut microbiome in mice. A 30-d PM treatment significantly reduced the diet-induced body weight gain and blood TAG levels (P<0·05) and improved glucose tolerance in male C57BL/6J mice. PM decreased lipopolysaccharides in blood and ameliorated local inflammation in the colon and the epididymal adipose tissue. Compared with low-fat and low-sucrose diet (LFD), HFD significantly reduced the mean number of species-level operational taxonomic units (OTU) per sample as well as species richness (P<0·05) but did not appear to affect other microbial diversity indices. Moreover, compared with LFD, HFD altered the abundance of approximately 23 % of the OTU detected (log10 linear discriminant analysis (LDA) score>2·0). PM also had a profound impact on the microbial composition in the gut microbiome and resulted in a distinct microbiome structure. For example, PM significantly increased the abundance of a probiotic bacterium, Lactobacillus reuteri (log10 LDA score>2·0). Together, our results suggest that PM may exert its immunoregulatory effects by enhancing proliferation of several species with probiotic activities while repressing the abundance of the microbial taxa that harbor potential pathogens. Our findings should facilitate mechanistic studies on PM as a potential bioactive compound to alleviate obesity and the metabolic syndrome.

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