Intestinal deletion of leptin signaling alters activity of nutrient transporters and delayed the onset of obesity in mice

Abstract

The importance of B-isoform of leptin receptor (LEPR-B) signaling in the hypothalamus, pancreas, or liver has been well characterized, but in the intestine, a unique site of entry for dietary nutrition into the body, it has been relatively ignored. To address this question, we characterized a mouse model deficient for LEPR-B specifically in intestinal epithelial cells (IECs).IEC LEPR-B-knockout (KO) and wild-type (WT) mice were generated by Cre-Lox strategy and fed a normal or high-fat diet (HFD). The analyses of the animals involved histology and immunohistochemistry of intestinal mucosa, indirect calorimetric measurements, whole-body composition, and expression and activities of nutrient transporters. IEC LEPR-B-KO mice exhibited a 2-fold increase in length of jejunal villi and have normal growth on a normal diet but were less susceptible (P<0.01) to HFD-induced obesity. No differences occurred in energy intake and expenditure between IEC LEPR-B-WT and -KO mice, but IEC LEPR-B-KO mice fed an HFD showed increased excreted fats (P<0.05). Activities of the Na ؉ /glucose cotransporter SGLT-1 and GLUT2 were unaffected in LEPR-B-KO jejunum, while GLUT5-mediated fructose transport and PepT1-mediated peptide transport were substantially reduced (P<0.01). These data demonstrate that intestinal LEPR-B signaling is important for the onset of diet-induced obesity.They suggest that intestinal LEPR-B could be a potential per os target for prevention against obesity.-

Increased Energy Expenditure, Lipolysis and Hyperinsulinemia Confer Resistance to Central Obesity and Type 2 Diabetes in Mice Lacking Alpha2α-Adrenoceptors

“…α 2A -/-Mice showed increased lipid output suggesting reduced fat absorption, and total small intestine length was also longer compared to that of WT animals. This phenotype combined to resistance to DIO resembles that of a mouse lacking leptin receptors in intestinal epithelial cells [56]. Whether the decreased fat absorption in α 2A -/-mice results from impaired α 2A -AR or leptin signalling in the gut warrants more detailed studies.…”

Altered intestinal neuroendocrine gene expression in humans with obesity

“…In a recent study gastric overexpression of the leptin gene, provoked by diet‐induced obesity, as well as oral leptin treatment increased intestinal mRNA TPH1 expression . Similarly, intestine‐specific deletion of leptin signaling reduced serotonin content in the duodenal mucosa and was also found to reduce intestinal nutrient transporters, as well as to delay the onset of obesity in mice fed with a high‐fat diet . On this background, one may speculate that the correlations of leptin with leptinR , GLP1R , nesfatin1 , and TPH1 in humans with obesity indicate an enhanced activity of the gastrointestinal leptin system which may contribute to the development and/or maintenance of obesity.…”

Recent discoveries on absorption of dietary fat: Presence, synthesis, and metabolism of cytoplasmic lipid droplets within enterocytes

“…Interestingly, a lack of functional leptin signaling also reduces TAG secretion and increases TAG storage in enterocytes through decreases in MTP activity and mRNA levels [107]. It also results in an increase in fecal fat excretion [203]. The specific role of leptin in regulating intestinal TAG metabolism and dietary fat absorption remains unclear.…”