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.—Tavernier, A., Cavin, J.‐B., Le Gall, M., Ducroc, R., Denis, R. G. P., Cluzeaud, F., Guilmeau, S., Sakar, Y., Barbot, L., Kapel, N., Le Beyec, J., Joly, F., Chua, S., Luquet, S., Bado, A. Intestinal deletion of leptin signaling alters activity of nutrient transporters and delayed the onset of obesity in mice. FASEB J. 28, 4100‐4110 (2014). www.fasebj.org

Bacterial lipopolysaccharides (LPS, endotoxins) are found in high amounts in the gut lumen. LPS can cross the gut barrier and pass into the blood (endotoxemia), leading to low-grade inflammation, a common scheme in metabolic diseases. Phospholipid transfer protein (PLTP) can transfer circulating LPS to plasma lipoproteins, thereby promoting its detoxification. However, the impact of PLTP on the metabolic fate and biological effects of gut-derived LPS is unknown. This study aimed to investigate the influence of PLTP on low-grade inflammation, obesity and insulin resistance in relationship with LPS intestinal translocation and metabolic endotoxemia. Wild-type (WT) mice were compared with Pltp-deficient mice (Pltp-KO) after a 4-month high-fat (HF) diet or oral administration of labeled LPS. On a HF diet, Pltp-KO mice showed increased weight gain, adiposity, insulin resistance, lipid abnormalities and inflammation, together with a higher exposure to endotoxemia compared to WT mice. After oral administration of LPS, PLTP deficiency led to increased intestinal translocation and decreased association of LPS to lipoproteins, together with an altered catabolism of triglyceride-rich lipoproteins (TRL). Our results show that PLTP, by modulating the intestinal translocation of LPS and plasma processing of TRL-bound LPS, has a major impact on low-grade inflammation and the onset of diet-induced metabolic disorders.