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

Abstract

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 on high long-chain triglyceride (LCT) diet, intestine-specific roles of GPR120 are unclear. To clarify the metabolic effect of GPR120 in 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 single administration of LCT. Under a high-LCT diet, GPR120int-/- mice showed 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.

Intestinal Morphology and Glucose Transporter Gene Expression under a Chronic Intake of High Sucrose

“…Villin-1 encodes the actin-binding protein Villin, which is expressed in intestinal epithelial cells [ 13 , 24 , 25 ]. Villin-1 reporter mice were generated by crossbreeding Villin-1-Cre transgenic mice and Ai14 homozygous mice (JAX stock #004586, #007908) (Jackson Laboratory, Bar Harbor, ME, USA).…”

“…Soon after the 10-week duration of the diet period, the mice were housed in cages without food, to match the fasting condition of the WT mice. ITTs were performed by the intraperitoneal injection of human regular insulin (100 U/mL, Eli Lilly and Company, Indianapolis, IN, USA) after fasting for 4 h [ 25 , 26 ]. Blood samples were taken at 0, 30, 60, 90, and 120 min from the tail vein after insulin administration.…”

“…Five equally spaced sections of 1 cm of small intestine were collected from the oral side (S1) to the anal side (S5) ( Supplementary Figure S1A ). Total RNAs of the small intestine were extracted with TRIzol reagent (Thermo Fisher Scientific, Waltham, MA, USA) [ 25 ]. Total RNAs were reverse transcribed using PrimerScript RT reagent Kit with gDNA Eraser (Takara Bio Inc., Kusatsu, Japan); mRNA expression levels were quantified by using cDNA dilution curves in real-time PCR with the ABI PRISM 7000 Sequence Detection System (Applied Biosystems Inc., Waltham, MA, USA).…”

“…Glucose levels were analyzed by the percent change from blood glucose levels at 0 min. OGTTs and OFTTs were performed after fasting for 16 h. Blood samples were collected at 0, 15, 30, 60, and 120 min from the tail vein after the oral administration of glucose and fructose (2 g/kg body weight) [25,27]. Blood glucose levels were measured by the glucose oxidase method (Sanwa Kagaku Kenkyusho Co., Ltd., Nagoya, Japan).…”

Effects of nutrient metabolism on pancreatic β‐cell mass and function: Recent findings

“…Lipid metabolism also has associations with β‐cell proliferation as well as insulin secretion. Several G protein‐coupled receptors (GPRs) activated by fatty acids have been identified 14 , 15 . GPR40/free fatty acid receptor 1 (FFAR1), a receptor for long‐chain free fatty acids (LCFAs), is expressed in β‐cells.…”