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Porcine adiponectin receptor 1 transgene resists high-fat/sucrose diet-induced weight gain, hepatosteatosis and insulin resistance in mice.

ABSTRACT: Adiponectin and its receptors have been demonstrated to play important roles in regulating glucose and lipid metabolism in mice. Obesity, type II diabetes and cardiovascular disease are highly correlated with down-regulated adiponectin signaling. In this study, we generated mice overexpressing the porcine Adipor1 transgene (pAdipor1) to study its beneficial effects in metabolic syndromes as expressed in diet-induced obesity, hepatosteatosis and insulin resistance. Wild-type (WT) and pAdipor1 transgenic mice were fed ad libitum with a standard chow diet (Chow) or a high-fat/sucrose diet (HFSD) for 24 weeks, beginning at 6 to 7 weeks of age. There were 12 mice per genetic/diet/sex group. When challenged with HFSD to induce obesity, the pAdipor1 transgenic mice resisted development of weight gain, hepatosteatosis and insulin resistance. These mice had lowered plasma adiponectin, triglyceride and glycerol concentrations compared to WT mice. Moreover, we found that (indicated by mRNA levels) fatty acid oxidation was enhanced in skeletal muscle and adipose tissue, and liver lipogenesis was inhibited. The pAdipor1 transgene also restored HFSD-reduced phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose transporter 4 mRNA in the adipose tissues, implying that the increased Pck1 may promote glyceroneogenesis to reduce glucose intolerance and thus activate the flux of glyceride-glycerol to resist diet-induced weight gain in the adipose tissues. Taken together, we demonstrated that pAdipor1 can prevent diet-induced weight gain and insulin resistance. Our findings may provide potential therapeutic strategies for treating metabolic syndromes and obesity, such as treatment with an ADIPOR1 agonist or activation of Adipor1 downstream targets.

SUBMITTER: Liu BH

PROVIDER: S-EPMC4160961 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Porcine adiponectin receptor 1 transgene resists high-fat/sucrose diet-induced weight gain, hepatosteatosis and insulin resistance in mice.

Liu Bing-Hsien BH Lin Yuan-Yu YY Wang Ya-Chin YC Huang Chao-Wei CW Chen Chih-Chien CC Wu Shinn-Chih SC Mersmann Harry J HJ Cheng Winston T K WT Ding Shih-Torng ST

Experimental animals 20130101 4

Adiponectin and its receptors have been demonstrated to play important roles in regulating glucose and lipid metabolism in mice. Obesity, type II diabetes and cardiovascular disease are highly correlated with down-regulated adiponectin signaling. In this study, we generated mice overexpressing the porcine Adipor1 transgene (pAdipor1) to study its beneficial effects in metabolic syndromes as expressed in diet-induced obesity, hepatosteatosis and insulin resistance. Wild-type (WT) and pAdipor1 tra ...[more]

PMID: 24172199

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Project description:BackgroundConsumption of added sugars has been considered a worldwide public health concern by its association with metabolic syndrome and its comorbidities. Meanwhile, current studies have suggested high-protein diets to promote weight loss and improved metabolic outcomes. Thus, this study aimed to investigate the effects of long-term high-protein diet (HPD, 34.3% protein) intake on high-sucrose-fed rats.MethodsWeaned male Wistar rats were randomized into two groups: rats fed a standard chow (CT/CT, 10% sucrose) or rats fed a high-sucrose diet (HSD, 25% sucrose) for a 20-week observational period. Subsequently, HS/HS animals were randomized into 3 new groups: rats maintained on HSD diet (HS/HS); rats submitted to HSD replacement by standard chow (HS/CT); and those with HSD replaced by HPD (HS/HP). All groups were followed up for 12 weeks during which we investigated the effects of HPD on body weight, energy intake, obesity development, glicemic/lipid profile, glucose tolerance, insulin resistance, tissue weight (adipose tissue, liver and skeletal muscles), lipolytic activity, liver lipoperoxidation and histology, as well as serum markers of hepatic function.ResultsPost-weaning exposure to HSD led to metabolic syndrome phenotype at adulthood, herein characterized by central obesity, glucose intolerance, dyslipidaemia and insulin resistance. Only HPD feeding was able to revert weight gain and adipose tissue accumulation, as well as restore adipose tissue lipolytic response to sympathetic stimulus. On the other hand, either HPD or withdrawal from HSD promoted very similar metabolic outcomes upon 12-week nutritional intervention. HS/HP and HS/CT rats showed reduced fasting serum levels of glucose, triacylglycerol and total cholesterol, which were correlated with the improvement of peripheral insulin sensitivity, as inferred from kITT and TyG Index values. Both nutritional interventions restored liver morphofunctional patterns, but only HPD restored lipid peroxidation.ConclusionsOur data showed that 12-week intake of an isocaloric moderately high-protein diet consistently restored high-sucrose-induced central adiposity and obesity in addition to the attenuation of other important metabolic outcomes, such as improvement of glucolipid homeostasis associated to increased insulin sensitivity and reversal of hepatic steatosis. On the other hand, simple withdrawal from high-sucrose consumption also promoted the abovementioned metabolic outcomes with no impact on body weight.

Project description:Acylethanolamides (NAEs) are bioactive lipids derived from diet fatty acids that modulate important homeostatic functions, including appetite, fatty acid synthesis, mitochondrial respiration, inflammation, and nociception. Among the naturally circulating NAEs, the pharmacology of those derived from either arachidonic acid (Anandamide), oleic acid (OEA), and palmitic acid (PEA) have been extensively characterized in diet-induced obesity. For the present work, we extended those studies to linoleoylethanolamide (LEA), one of the most abundant NAEs found not only in plasma and body tissues but also in foods such as cereals. In our initial study, circulating concentrations of LEA were found to be elevated in overweight humans (body mass index (BMI, Kg/m2) > 25) recruited from a representative population from the south of Spain, together with AEA and the endocannabinoid 2-Arachidonoyl glycerol (2-AG). In this population, LEA concentrations correlated with the circulating levels of cholesterol and triglycerides. In order to gain insight into the pharmacology of LEA, we administered it for 14 days (10 mg/kg i.p. daily) to obese male Sprague Dawley rats receiving a cafeteria diet or a standard chow diet for 12 consecutive weeks. LEA treatment resulted in weight loss and a reduction in circulating triglycerides, cholesterol, and inflammatory markers such as Il-6 and Tnf-alpha. In addition, LEA reduced plasma transaminases and enhanced acetyl-CoA-oxidase (Acox) and Uncoupling protein-2 (Ucp2) expression in the liver of the HFD-fed animals. Although the liver steatosis induced by the HFD was not reversed by LEA, the overall data suggest that LEA contributes to the homeostatic signals set in place in response to diet-induced obesity, potentially contributing with OEA to improve lipid metabolism after high fat intake. The anti-inflammatory response associated with its administration suggests its potential for use as a nutrient supplement in non-alcoholic steatohepatitis.

Dataset Information

Porcine adiponectin receptor 1 transgene resists high-fat/sucrose diet-induced weight gain, hepatosteatosis and insulin resistance in mice.

Publications

Porcine adiponectin receptor 1 transgene resists high-fat/sucrose diet-induced weight gain, hepatosteatosis and insulin resistance in mice.

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