Nutrient sensing is a mechanism for organisms to sense their environment. In larger animals, including humans, the intestinal tract is a major site of nutrient sensing for the body, not surprisingly, as this is the central location where nutrients are absorbed. In the gut, bacterial fermentation results in generation of short chain fatty acids (SCFAs), a class of nutrients, which are sensed by specific membrane bound receptors, FFA2, FFA3, GPR109a, and Olfr78. These receptors are expressed uniquely throughout the gut and signal through distinct mechanisms. To date, the emerging data suggests a role of these receptors in normal and pathological conditions. The overall function of these receptors is to regulate aspects of intestinal motility, hormone secretion, maintenance of the epithelial barrier, and immune cell function. Besides in intestinal health, a prominent role of these receptors has emerged in modulation of inflammatory and immune responses during pathological conditions. Moreover, these receptors are being revealed to interact with the gut microbiota. This review article updates the current body of knowledge on SCFA sensing receptors in the gut and their roles in intestinal health and disease as well as in whole body energy homeostasis. © 2017 American Physiological Society.Compr Physiol8:1091‐1115, 2018.

Glucose phosphorylation by hexokinases traps glucose in cells and facilitates its usage in metabolic processes dependent on cellular needs. Hexokinase domain containing protein-1 (HKDC1) is a recently discovered protein with wide expression containing hexokinase activity, first noted through a genome-wide association study to be linked with gestational glucose homeostasis during pregnancy. Since then, HDKC1 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, 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.

Glucokinase (GCK) is the principal hexokinase (HK) in the liver, operating as a glucose sensor to regulate glucose metabolism and lipid homeostasis. Recently, we proposed Hexokinase Domain Containing-1 (HKDC1) to be a novel 5^th HK with expression in the liver. Here, we reveal HKDC1 to have low glucose-phosphorylating ability and demonstrate its association with the mitochondria in hepatocytes. As we have shown previously that genetic deletion of HKDC1 leads to altered hepatic triglyceride levels, we also explored the influence of overexpression of HKDC1 in hepatocytes on cellular metabolism observing reduced glycolytic capacity and maximal mitochondrial respiration with concurrent reductions in glucose oxidation and mitochondrial membrane potential. Furthermore, we found that acute in vivo overexpression of HKDC1 in the liver induced significant changes in mitochondrial dynamics. Altogether, these findings suggest overexpression of HKDC1 causes mitochondrial dysfunction in hepatocytes. However, its overexpression was not enough to alter energy storage in the liver, but led to mild improvement in glucose tolerance. We next investigated the conditions necessary to induce HKDC1 expression, observing HKDC1 expression to be elevated in human patients whose livers were at more advanced stages of NAFLD and similarly found high liver expression in mice on diets causing high levels of liver inflammation and fibrosis. Overall, our data suggests HKDC1 expression in hepatocytes results in defective mitochondrial function and altered hepatocellular metabolism and speculate that its expression in liver may play a role in the development of NAFLD.

Liver cancer (LC) is the fourth leading cause of death from cancer malignancies. Recently, a putative fifth hexokinase, hexokinase domain containing 1 (HKDC1), was shown to have significant overexpression in LC compared to healthy liver tissue. Using a combination of in vitro and in vivo tools, we examined the role of HKDC1 in LC development and progression. Importantly, HKDC1 ablation stops LC development and progression via its action at the mitochondria by promoting metabolic reprogramming and a shift of glucose flux away from the TCA cycle. HKDC1 ablation leads to mitochondrial dysfunction resulting in less cellular energy, which cannot be compensated by enhanced glucose uptake. Moreover, we show that the interaction of HKDC1 with the mitochondria is essential for its role in LC progression, and without this interaction, mitochondrial dysfunction occurs. As HKDC1 is highly expressed in LC cells, but only to a minimal degree in hepatocytes under normal conditions, targeting HKDC1, specifically its interaction with the mitochondria, may represent a highly selective approach to target cancer cells in LC.

While some of the variance observed in adiposity and weight change within populations can be accounted for by traditional risk factors, a new factor, the gut microbiota, has recently been associated with obesity. However, the causal mechanisms through which the gut microbiota and its metabolites, short chain fatty acids (SCFAs) influence obesity are unknown, as are the individual obesogenic effects of the individual SCFAs (butyrate, acetate and propionate). This study, METS-Microbiome, proposes to examine the influence of novel risk factors, the gut microbiota and SCFAs, on obesity, adiposity and weight change in an international established cohort spanning the epidemiologic transition. The parent study; Modeling the Epidemiologic Transition Study (METS) is a well-established and ongoing prospective cohort study designed to assess the association between body composition, physical activity, and relative weight, weight gain and cardiometabolic disease risk in five diverse population-based samples in 2500 people of African descent. The cohort has been prospectively followed since 2009. Annual measures of obesity risk factors, including body composition, objectively measured physical activity and dietary intake, components which vary across the spectrum of social and economic development. In our new study; METS-Microbiome, in addition to continuing yearly measures of obesity risk, we will also measure gut microbiota and stool SCFAs in all contactable participants, and follow participants for a further 3 years, thus providing one of the largest gut microbiota population-based studies to date. This new study capitalizes upon an existing, extensively well described cohort of adults of African-origin, with significant variability as a result of the widespread geographic distributions, and therefore variation in the environmental covariate exposures. The METS-Microbiome study will substantially advance the understanding of the role gut microbiota and SCFAs play in the development of obesity and provide novel obesity therapeutic targets targeting SCFAs producing features of the gut microbiota. Registered NCT03378765 Date first posted: December 20, 2017.

Olfactory receptor-78 (Olfr-78) is a recently identified G protein-coupled receptor activated by short-chain fatty acids acetate and propionate. A suggested role for this receptor exists in the prostate where it may influence chronic inflammatory response leading to intraepithelial neoplasia. Olfr-78 has also been shown to be expressed in mouse colon. Short-chain fatty acids and their receptors are well known to modulate inflammation in the gut. Considering this possibility, we first explored if colitis regulated Olfr-78 expression in the gut, where we observed a significant reduction in the expression of Olfr-78 transcript in mouse models of dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. To more directly test this, mice deficient in Olfr-78 were administered with DSS in water for 7 days and were found to have increased expression of IL-1β and inflammatory signs in colon compared with control mice. Next, we explored the expression of its human counterpart olfactory receptor family 51, subfamily E, member 2 (OR51E2) in human intestinal samples and observed that it was in fact also expressed in human colon samples. RNA sequence analysis revealed significant changes in the genes involved in infection, immunity, inflammation, and colorectal cancer between wild-type and Olfr-78 knockout mice. Collectively, our findings show that Olfr-78 is highly expressed in colon and downregulated in DSS- and TNBS-induced colitis, and DSS-treated Olfr-78 null mice had increased colonic expression of cytokine RNA levels, suggesting a potential role for this receptor in intestinal inflammation. Future investigations are needed to understand how Olfr-78/OR51E2 in both mouse and human intestine modulates gastrointestinal pathophysiology.