Enhancing enterocyte fatty acid oxidation in mice affects glycemic control depending on dietary fat

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.

Omega-3 Phospholipids from Krill Oil Enhance Intestinal Fatty Acid Oxidation More Effectively than Omega-3 Triacylglycerols in High-Fat Diet-Fed Obese Mice

“…In our study, krill oil administration stimulated palmitate oxidation in only one of the five small intestine segments analyzed (i.e., proximal ileum). Despite previous reports showing that constitutive up-regulation of FA β-oxidation throughout the intestine but not selectively in the proximal ileum improved whole-body glucose homeostasis [16], we observed improved glucose tolerance only in mice fed the ω3PL-H diet. Thus, it is more likely that segment-specific stimulation of FA oxidation is closely related to the regulation of intestinal TAG transport, as observed after activation of PPARα in the small intestine by fenofibrate [76].…”

“…For instance, fish oil supplementation (i.e., Omega-3 as TAG) induced dose-dependent expression of genes involved in lipid metabolism and FA oxidation in the small intestine but not in the colon of C57BL/6 mice fed a high-fat diet [14]. Enhancement of FA oxidation in the intestine has been shown to protect mice from visceral fat accumulation and impaired glucose homeostasis induced by high-fat feeding [16]. These data suggest that the small intestine may contribute significantly to the metabolic, antisteatotic and possibly also the anti-obesity effects of Omega-3 administration.…”

Organoids to Study Intestinal Nutrient Transport, Drug Uptake and Metabolism – Update to the Human Model and Expansion of Applications

“…Stable isotope labeling enables following the fate of the labeled fatty acid within the enterocyte, being either subjected to chain-shortening during beta-oxidation and conversion to the respective acylcarnitine species for energy generation, or being reesterified, and incorporated into chylomicrons for systemic supply. Importantly, sensing dietary fat via fatty acid oxidation in enterocytes has been implicated in the control of eating ( Langhans et al, 2011 ), and modulation of enterocyte metabolism might affect whole body glucose homeostasis and the development of diet-induced obesity ( Schober et al, 2013 ; Ramachandran et al, 2018 ). Prior to addition of d31-labeled palmitic acid, murine small intestinal organoids were incubated with CCM prepared with low-glucose DMEM/F12 for 24 h. Low-glucose DMEM/F12 contains 1g/L glucose, corresponding to 5.5 mM glucose, which is within the physiological range.…”

“…For example, peptidomimetics like β-lactam antibiotics are substrates of peptide transporters ( Wenzel et al, 2002 ), and a broad range of drugs is metabolized by intestinal cytochrome P450 enzymes ( Xie et al, 2016 ). Furthermore, IEC not only constitute a barrier separating the host from its microbiota, epithelial metabolism serves as a gatekeeper of nutrient availability for the whole organism, and IEC fatty acid oxidation has been implicated in the control of eating ( Langhans et al, 2011 ; Ramachandran et al, 2018 ). Yet, many aspects of nutrient absorption, drug bioavailability and enterocyte metabolism remain elusive, e.g., underlying causes of fructose malabsorption are still unknown ( Ebert and Witt, 2016 ) and a model to predict the impact of chemical modifications of a drug on its oral bioavailability is missing ( Ovadia et al, 2011 ; Rader et al, 2018b ).…”

Emerging Role of Lymphatics in the Regulation of Intestinal Lipid Mobilization

“…The details of both CM assembly and CLD metabolism have been reviewed elsewhere (Hussain, 2014;Beilstein et al, 2015;D'Aquila et al, 2016). Besides CM secretion and storage in CLDs, dietary fatty acids are also oxidized in enterocytes to generate ketone bodies (Uchida et al, 2011; Schober et al, 2013), a capacity that is well-developed during the suckling period in rodents, disappears at weaning, and can be re-established upon high-fat feeding (Thumelin et al, 1993;Clara et al, 2017;Ramachandran et al, 2018). A high capacity to oxidize dietary fat may translate into a lower risk of weight gain on high fat diets (Kondo et al, 2006).…”