GPR41 and GPR43 in Obesity and Inflammation – Protective or Causative?

Abstract

GPR41 and GPR43 are a pair of mammalian G protein-coupled receptors (GPCRs) expressed in human adipocytes, colon epithelial cells, and peripheral blood mononuclear cells. These receptors are activated by short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate – which are produced during dietary fiber fermentation by resident gut bacteria. This unique ligand specificity suggests that GPR41 and GPR43 may mediate the interaction between the human host and the gut microbiome. Indeed, studies on knockout mice implicate GPR41 and GPR43 in chronic inflammatory disorders such as obesity, colitis, asthma and arthritis. However, whether GPR41 and GPR43 are protective or causative is inconsistent between studies. This discrepancy may be due to differences in the disease models used, the inbred mouse strains, or non-specific knockout effects. Here, we review the latest findings on GPR41 and GPR43, highlighting contradictory observations. With GPR41 and GPR43 being considered as drug targets, it is pertinent that their role is fully elucidated. We propose that future studies on human tissues, ex vivo, may allow us to confirm the role of GPR41 and GPR43 in humans, be it protective or causative.

The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis?

“…They are also frequently found on adipocytes, where they regulate adipogenesis and lipolysis (Ang and Ding, 2016;Yonezawa et al, 2013), although there are conflicting reports in the literature as to the exact mechanisms of this effect (Rumberger et al, 2014;Taggart et al, 2005). Notably, at least FFAR3 and HCAR2 expression is regulated by DNA methylation (Remely et al, 2014;Thangaraju et al, 2009) and FFAR3 has been shown to be increased in blood leukocytes in obese and type-II-diabetes patients, potentially leading to reduced satiety signalling via SCFA-induced leptin production in adipocytes (Remely et al, 2014).…”

Short Chain Fatty Acids Prevent High-fat-diet-induced Obesity in Mice by Regulating G Protein-coupled Receptors and Gut Microbiota

“…SCFAs also act as signal transduction molecules and bind and activate orphan G-protein-coupled receptors, such as GPR43 and GPR41, which are also known as free fatty acid receptor 2 and 3 (FFAR2 and FFAR3), respectively. GPR43 and GPR41 are both widely expressed in the small intestine and colon, as well as tissues and organs beyond the gut1516. However, there is some debate regarding the role of these receptors in the regulation of energy balance in vivo .…”

“…Inconsistently, high-fat diet (HFD)-fed GPR43-deficient mice were shown to have lower body fat mass and increased lean body mass accompanied by improved insulin sensitivity and increased energy expenditure compared to those of the normal diet-fed mice18. Thus, the protective or causative effects of GPR43 in obesity need to be clarified16.…”

Gut Microbiome and Colon Cancer: Role of Bacterial Metabolites and Their Molecular Targets in the Host

“…The roles of GPR41 and GPR43, which are activated by all three short-chain fatty acids, remain unclear [40]. GPR41 is expressed in colonic epithelial cells as well as in enteroendocrine cells, [41] whereas GPR43 is expressed in colonic epithelial cells, enteroendocrine cells, and immune cells [42, 43].…”