Abstract
Studies indicate that modulating enterocyte metabolism might affect whole body glucose homeostasis and the development of diet-induced obesity (DIO). We tested whether enhancing enterocyte fatty acid oxidation (FAO) could protect mice from DIO and impaired glycemic control. To this end, we used mice expressing a mutant form of carnitine palmitoyltransferase-1a (CPT1mt), insensitive to inhibition by malonyl-CoA, in their enterocytes (iCPT1mt) and fed them low-fat control diet (CD) or high-fat diet (HFD) chronically. CPT1mt expression led to an upregulation of FAO in the enterocytes. On CD, iCPT1mt mice had impaired glycemic control and showed concomitant activation of lipogenesis, glycolysis and gluconeogenesis in their enterocytes. On HFD, both iCPT1mt and control mice developed DIO, but iCPT1mt mice showed improved glycemic control and reduced visceral fat mass. Together these data indicate that modulating enterocyte metabolism in iCPT1mt mice affects glycemic control in a body weight-independent, but dietary fat-dependent manner.
Highlights
Obesity and its related comorbidities, such as type-2-diabetes (T2D), hypertension, and cardiovascular disease, are major global health concerns[1]
Western blot analysis of tissue samples from Cpt1mtfl/fl and iCPT1mt mice fed control diet (CD) and high-fat diet (HFD) indicated that the CPT1mt protein was expressed in the enterocytes of the duodenum and jejunum, but not in the liver of iCPT1mt mice (P < 0.0001 for CD duodenum and jejunum; P < 0.05 for HFD duodenum and jejunum) (Fig. 1A,B)
When fed HFD for 3 days, primary enterocytes from the duodenum of iCPT1mt mice showed a lower rate of palmitate oxidation compared to Cpt1mtfl/fl mice (P < 0.001), but the enterocytes from the jejunum of iCPT1mt mice showed an enhanced palmitate oxidation rate compared to controls (P < 0.0001) (Fig. 2A)
Summary
Obesity and its related comorbidities, such as type-2-diabetes (T2D), hypertension, and cardiovascular disease, are major global health concerns[1]. The only treatments for morbid obesity that lead to sustained weight loss are invasive and costly interventions such as gastric bypass surgery[2]. The success of these surgical procedures comes with several unresolved side effects, including malabsorption of essential micronutrients and early or late post-surgical complications[2]. We recently reported evidence that a constitutive overexpression of the mitochondrial protein Sirtuin 3 (SIRT3) in mouse enterocytes was associated with enhanced FAO and ketogenesis and reduced fatty acid synthesis in these cells when the mice were fed a fat-rich diet[9]. Control diet (CD) or a high-fat diet (HFD) for several weeks, and phenotyped them to determine whether enterocyte CPT1mt expression could protect these mice from developing impaired glucose homeostasis, IR and DIO
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