Modulating Enterocyte Metabolism Affects Whole Body Glucose Homeostasis in Mice

Abstract

Obesity and its comorbidities are a growing concern in today’s world. Obesity and overweight increase the risk of developing several life threatening diseases, the risks of which are decreased significantly even with a moderate weight loss. The most common comorbidity of obesity is type-2 diabetes which involves a severe dysfunction in glycemic control. Several studies suggest that gut metabolism plays an important role in whole body energy metabolism. Data from peripheral administration of drugs that reduced food intake in rodents showed that the inhibition of eating was associated with increased fatty acid oxidation (FAO) and ketogenesis in the small intestine, but not in the liver. Gastric bypass studies in humans and rodents indicate that the restructuring of the small intestine leads to morphological and metabolic changes in the gut. These changes are associated with the almost immediate reversal of the diabetic phenotype seen post-surgery, which is absent or less pronounced in surgeries like gastric banding that do not involve these dramatic changes in the small intestine. The intestinal mucosa, or rather the epithelial cells in the small intestine, are the main cells that absorb nutrients from the diet, and redistribute them for storage or to immediately fuel metabolism in the rest of the body. Enteroendocrine cells in the gut epithelium respond to different nutritional and metabolic cues and release gut hormones that also control eating behavior and regulate glucose homeostasis. All these factors led us to hypothesize that modulating enterocyte metabolism by upregulating FAO in these cells might affect the development of diet-induced obesity (DIO) and impaired glucose homeostasis. To test this we developed two different transgenic mouse models to upregulate enterocyte FAO. Using the cre-loxP system, we overexpressed the mitochondrial protein Sirtuin 3 (SIRT3) or expressed a mutant 11 form of the mitochondrial protein carnitine palmitoyltransferase-1 (CPT1mt) in the enterocytes of mice. We phenotyped these mice under conditions of low-fat control diet (CD) or high-fat diet (HFD) feeding. Our results show that constitutive (over)expression of SIRT3 or CPT1mt in mouse enterocytes had no effects on body weight gain and the development of DIO. Also, enterocyte SIRT3 expression did not affect glycemic control in CD-fed mice, but improved insulin sensitivity and glucose tolerance in HFD-fed mice, despite the development of DIO. Conversely, enterocyte specific CPT1mt expression led to impaired glucose homeostasis in CD-fed mice, but improved it in HFD-fed mice with DIO. Together our results indicate that modulating enterocyte metabolism can affect whole body glucose homeostasis differentially independent of body weight, but dependent on the nutritional content of the diet. --> Obesity and its comorbidities are a growing concern in today’s world. Obesity and overweight increase the risk of developing several life threatening diseases, the risks of which are decreased significantly even with a moderate weight loss. The most common comorbidity of obesity is type-2 diabetes which involves a severe dysfunction in glycemic control.Several studies suggest that gut metabolism plays an important role in whole body energy metabolism. Data from peripheral administration of drugs that reduced food intake in rodents showed that the inhibition of eating was associated with increased fatty acid oxidation (FAO) and ketogenesis in the small intestine, but not in the liver. Gastric bypass studies in humans and rodents indicate that the restructuring of the small intestine leads to morphological and metabolic changes in the gut. These changes are associated with the almost immediate reversal of the diabetic phenotype seen post-surgery, which is absent or less pronounced in surgeries like gastric banding that do not involve these dramatic changes in the small intestine. The intestinal mucosa, or rather the epithelial cells in the small intestine, are the main cells that absorb nutrients from the diet, and redistribute them for storage or to immediately fuel metabolism in the rest of the body. Enteroendocrine cells in the gut epithelium respond to different nutritional and metabolic cues and release gut hormones that also control eating behavior and regulate glucose homeostasis.All these factors led us to hypothesize that modulating enterocyte metabolism by upregulating FAO in these cells might affect the development of diet-induced obesity (DIO) and impaired glucose homeostasis. To test this we developed two different transgenic mouse models to upregulate enterocyte FAO. Using the cre-loxP system, we overexpressed the mitochondrial protein Sirtuin 3 (SIRT3) or expressed a mutant form of the mitochondrial protein carnitine palmitoyltransferase-1 (CPT1mt) in the enterocytes of mice. We phenotyped these mice under conditions of low-fat control diet (CD) or high-fat diet (HFD) feeding.Our results show that constitutive (over)expression of SIRT3 or CPT1mt in mouse enterocytes had no effects on body weight gain and the development of DIO. Also, enterocyte SIRT3 expression did not affect glycemic control in CD-fed mice, but improved insulin sensitivity and glucose tolerance in HFD-fed mice, despite the development of DIO. Conversely, enterocyte specific CPT1mt expression led to impaired glucose homeostasis in CD-fed mice, but improved it in HFD-fed mice with DIO. Together our results indicate that modulating enterocyte metabolism can affect whole body glucose homeostasis differentially independent of body weight, but dependent on the nutritional content of the diet.