Intestinal FFA3 mediates obesogenic effects in mice on a Western diet.

Free fatty acid receptor 3 (FFA3) is a recently-deorphanized G-protein-coupled receptor. Its ligands are short-chain fatty acids (SCFAs), which are key nutrients derived from the gut microbiome fermentation process that play diverse roles in the regulation of metabolic homeostasis and glycemic control. FFA3 is highly expressed within the intestine, where its role and its effects on physiology and metabolism are unclear. Previous in vivo studies involving this receptor have relied on global knockout mouse models, making it difficult to isolate intestine-specific roles of FFA3. To overcome this challenge, we generated an intestine-specific knockout mouse model for FFA3, Villin-Cre-FFA3 (Vil-FFA3). Model validation and general metabolic assessment of male mice fed a standard chow diet revealed no major congenital defects. Because dietary changes are known to alter gut microbial composition, and thereby SCFA production, an obesogenic challenge was performed on male Vil-FFA3 mice and their littermate controls to probe for a phenotype on a high-fat, high-sugar "Western diet" (WD) compared with a low-fat control diet (CD). Vil-FFA3 mice versus FFA3fl/fl controls on WD, but not CD, were protected from the development of diet-induced obesity and exhibited significantly less fat mass as well as smaller adipose depositions and adipocytes. Although overall glycemic control was unchanged in the WD-fed Vil-FFA3 group, fasted glucose levels trended lower. Intestinal inflammation was significantly reduced in the WD-fed Vil-FFA3 mice, supporting protection from obesogenic effects. Furthermore, we observed lower levels of gastric inhibitory protein (GIP) in the WD-fed Vil-FFA3 mice, which may contribute to phenotypic changes. Our findings suggest a novel role of intestinal FFA3 in promoting the metabolic consequences of a WD, including the development of obesity and inflammation. Moreover, these data support an intestine-specific role of FFA3 in whole body metabolic homeostasis and in the development of adiposity.NEW & NOTEWORTHY Here, we generated a novel intestine-specific knockout mouse model for FFA3 (Vil-FFA3) and performed a comprehensive metabolic characterization of mice in response to an obesogenic challenge. We found that Vil-FFA3 mice fed with a Western diet were largely protected from obesity, exhibiting significantly lower levels of fat mass, lower intestinal inflammation, and altered expression of intestinal incretin hormones. Results support an important role of intestinal FFA3 in contributing to metabolism and in the development of diet-induced obesity.

The Role of Hexokinase Domain Containing Protein-1 in Glucose Regulation During Pregnancy.

PURPOSE OF REVIEW: Gestational diabetes mellitus (GDM) is a common pregnancy complication conferring an increased risk to the individual of developing type 2 diabetes. As such, a thorough understanding of the pathophysiology of GDM is warranted. Hexokinase domain containing protein-1 (HKDC1) is a recently discovered protein containing hexokinase activity which has been shown to be associated with glucose metabolism during pregnancy. Here, we discuss recent evidence suggesting roles for the novel HKDC1 in gestational glucose homeostasis and the development of GDM and overt diabetes. RECENT FINDINGS: Genome-wide association studies identified variants of the HKDC1 gene associated with maternal glucose metabolism. Studies modulating HKDC1 protein expression in pregnant mice demonstrate that HKDC1 has roles in whole-body glucose utilization and nutrient balance, with liver-specific HKDC1 influencing insulin sensitivity, glucose tolerance, gluconeogenesis, and ketone production. HKDC1 has important roles in maintaining maternal glucose homeostasis extending beyond traditional hexokinase functions and may serve as a potential therapeutic target.

Intestinal FFA2 promotes obesity by altering food intake in Western diet-fed mice.

Short-chain fatty acids (SCFAs) are key nutrients that play a diverse set of roles in physiological function, including regulating metabolic homeostasis. Generated through the fermentation of dietary fibers in the distal colon by the gut microbiome, SCFAs and their effects are partially mediated by their cognate receptors, including free fatty acid receptor 2 (FFA2). FFA2 is highly expressed in the intestinal epithelial cells, where its putative functions are controversial, with numerous in vivo studies relying on global knockout mouse models to characterize intestine-specific roles of the receptor. Here, we used the Villin-Cre mouse line to generate a novel, intestine-specific knockout mouse model for FFA2 (Vil-FFA2) to investigate receptor function within the intestine. Because dietary changes are known to affect the composition of the gut microbiome, and can thereby alter SCFA production, we performed an obesogenic challenge on male Vil-FFA2 mice and their littermate controls (FFA2-floxed, FFA2fl/fl) to identify physiological changes on a high-fat, high-sugar 'Western diet' (WD) compared to a low-fat control diet (CD). We found that the WD-fed Vil-FFA2 mice were transiently protected from the obesogenic effects of the WD and had lower fat mass and improved glucose homeostasis compared to the WD-fed FFA2fl/fl control group during the first half of the study. Additionally, major differences in respiratory exchange ratio and energy expenditure were observed in the WD-fed Vil-FFA2 mice, and food intake was found to be significantly reduced at multiple points in the study. Taken together, this study uncovers a novel role of intestinal FFA2 in mediating the development of obesity.

Hexokinase domain-containing protein-1 in metabolic diseases and beyond.

Glucose phosphorylation by hexokinases (HKs) traps glucose in cells and facilitates its usage in metabolic processes dependent on cellular needs. HK domain-containing protein-1 (HKDC1) is a recently discovered protein with wide expression containing HK activity, first noted through a genome-wide association study (GWAS) to be linked with gestational glucose homeostasis during pregnancy. Since then, HKDC1 has been observed to be expressed in many human tissues. Moreover, studies have shown that HKDC1 plays a role in glucose homeostasis by which it may affect the progression of many pathophysiological conditions such as gestational diabetes mellitus (GDM), nonalcoholic steatohepatitis (NASH), and cancer. Here, we review the key studies contributing to our current understanding of the roles of HKDC1 in human pathophysiological conditions and potential therapeutic interventions.