Inhibition of GPR120 signaling in intestine ameliorates insulin resistance and fatty liver under high-fat diet feeding.

G protein-coupled receptor (GPR) 120 is expressed in enteroendocrine cells secreting glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP), and cholecystokinin (CCK). Although GPR120 signaling in adipose tissue and macrophages has been reported to ameliorate obesity and insulin resistance in a high long-chain triglyceride (LCT) diet, intestine-specific roles of GPR120 are unclear. To clarify the metabolic effect of GPR120 in the intestine, we generated intestine-specific GPR120-knockout (GPR120int-/-) mice. In comparison with floxed GPR120 (WT) mice, GPR120int-/- mice exhibited reduced GIP secretion and CCK action without change of insulin, GLP-1, or peptide YY (PYY) secretion after a single administration of LCT. Under a high-LCT diet, GPR120int-/- mice showed a mild reduction of body weight and substantial amelioration of insulin resistance and fatty liver. Moreover, liver and white adipose tissue (WAT) of GPR120int-/-mice exhibited increased Akt phosphorylation and reduced gene expression of suppressor of cytokine signaling (SOCS) 3, which inhibits insulin signaling. In addition, gene expression of inflammatory cytokines in WAT and lipogenic molecules in liver were reduced in GPR120int-/- mice. These findings suggest that inhibition of GPR120 signaling in intestine ameliorates insulin resistance and fatty liver under high-LCT diet feeding.NEW & NOTEWORTHY We generated novel intestine-specific GPR120-knockout (GPR120int-/-) mice and investigated the metabolic effect of GPR120 in the intestine. GPR120int-/- mice exhibited a reduction of GIP secretion and CCK action after a single administration of LCT. Under a high-LCT diet, GPR120int-/- mice showed mild improvement in obesity and marked amelioration of insulin resistance and hepatic steatosis. Our results indicate an important role of intestinal GPR120 on insulin resistance and hepatic steatosis.

Noninvasive Evaluation of GIP Effects on ß-Cell Mass Under High-Fat Diet.

Pancreatic ß-cell mass (BCM) has an importance in the pathophysiology of diabetes mellitus. Recently, glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged as a promising tool for BCM evaluation. While glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is known to be involved in high-fat diet (HFD)-induced obesity, the effect of GIP on BCM is still controversial. In this study, we investigated indium 111 (111In)-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4) single-photon emission computed tomography/computed tomography (SPECT/CT) as a tool for evaluation of longitudinal BCM changes in HFD-induced obese mice, at the same time we also investigated the effects of GIP on BCM in response to HFD using GIP-knockout (GIP-/-) mice. 111In-exendin-4 SPECT/CT was able to distinguish control-fat diet (CFD)-fed mice from HFD-fed mice and the pancreatic uptake values replicated the BCM measured by conventional histological methods. Furthermore, BCM expansions in HFD-fed mice were demonstrated by time-course changes of the pancreatic uptake values. Additionally, 111In-exendin-4 SPECT/CT demonstrated the distinct changes in BCM between HFD-fed GIP-/- (GIP-/-+HFD) and wild-type (WT+HFD) mice; the pancreatic uptake values of GIP-/-+HFD mice became significantly lower than those of WT+HFD mice. The different changes in the pancreatic uptake values between the two groups preceded those in fat accumulation and insulin resistance. Taken together with the finding of increased ß-cell apoptosis in GIP-/-+HFD mice compared with WT+HFD mice, these data indicated that GIP has preferable effects on BCM under HFD. Therefore, 111In-exendin-4 SPECT/CT can be useful for evaluating increasing BCM and the role of GIP in BCM changes under HFD conditions.

Carbonic anhydrase 8 (CAR8) negatively regulates GLP-1 secretion from enteroendocrine cells in response to long-chain fatty acids.

Glucagon-like peptide-1 (GLP-1) is an incretin secreted from enteroendocrine preproglucagon (PPG)-expressing cells (traditionally known as L cells) in response to luminal nutrients that potentiates insulin secretion. Augmentation of endogenous GLP-1 secretion might well represent a novel therapeutic target for diabetes treatment in addition to the incretin-associated drugs currently in use. In this study, we found that PPG cells substantially express carbonic anhydrase 8 (CAR8), which has been reported to inhibit inositol 1,4,5-trisphosphate (IP3) binding to the IP3 receptor and subsequent Ca2+ efflux from the endoplasmic reticulum in neuronal cells. In vitro experiments using STC-1 cells demonstrated that Car8 knockdown increases long-chain fatty acid (LCFA)-stimulated GLP-1 secretion. This effect was reduced in the presence of phospholipase C (PLC) inhibitor; in addition, Car8 knockdown increased the intracellular Ca2+ elevation caused by α-linolenic acid, indicating that CAR8 exerts its effect on GLP-1 secretion via the PLC/IP3/Ca2+ pathway. Car8wdl null mutant mice showed significant increase in GLP-1 response to oral corn oil administration compared with that in wild-type littermates, with no significant change in intestinal GLP-1 content. These results demonstrate that CAR8 negatively regulates GLP-1 secretion from PPG cells in response to LCFAs, suggesting the possibility of augmentation of postprandial GLP-1 secretion by CAR8 inhibition.NEW & NOTEWORTHY This study focused on the physiological significance of carbonic anhydrase 8 (CAR8) in GLP-1 secretion from enteroendocrine preproglucagon (PPG)-expressing cells. We found an inhibitory role of CAR8 in LCFA-induced GLP-1 secretion in vitro and in vivo, suggesting a novel therapeutic approach to diabetes and obesity through augmentation of postprandial GLP-1 secretion by CAR8 inhibition.