Orphan G-protein-coupled Receptors in the Kidney and Adipose Tissue
More recently, orphan G-protein-coupled receptors (GPCRs) have been shown to play a role in the progression of obesity-related disease. These receptors function as receptors for short-chain fatty acids (SCFAs), such as acetate and propionate. The source of FA can be diverse. They can come from the digestion and lipolysis of triglycerides in the liver and adipose tissue, or be obtained from food intake. The GPCRs are expressed in many tissues such as the pancreas, adipose tissue, and kidney. In the pancreas, the orphan GPCRs, especially GPR40, have been found to interact with insulin signaling. A recent study showed that an acute exposure of FFA stimulated insulin release from the β cells, whereas chronic stimulation by FFA impaired the β-cell insulin secretion and led to lipotoxicity. In that study, transgenic GPR40 knockout mice were protected from hyperinsulinemia and glucose intolerance. It is thus easy to conclude that excess food intake, and especially fat food, lead to an increase of FFAs that, in turn, promote abnormal response in their orphan GPCRs, promoting impaired insulin secretion. In adipose tissue, GPR43 and GPR41 have been identified. Their exact role is not fully elucidated. Xiong et al. found that the activation of GPR41 by SCFAs induced leptin expression in both mouse adipocyte cell line and mouse adipose tissue in primary culture. The increased level of circulating leptin was also measured in mice after acute oral administration of propionate, a well-known SCFA, ligand of the GPCRs, therefore suggesting that SCFA via a specific GPC receptor could play a role in the cellular signaling pathway and regulate metabolic factor such as leptin. In another study, increased expression of GPR43 but not GPR41 was demonstrated in adipose tissue from mice fed a HFD. Moreover, the inhibition of GPR43 in 3T3-L cells by specific siRNA was found to significantly reduce lipid accumulation after stimulation with the SCFA, propionate. The role of GPR43 activation in the inhibition of lipolysis was then confirmed using an in-vitro model of adipocytes isolated from GPR43 knockout mice. Furthermore, in vivo, activating GPR43 by SCFA resulted in a reduced level of plasma FFA, reinforcing the role of GPR43 in inhibiting lipolysis and reducing plasma FFA. In the kidney, the evidence for a role of GPCR has been reported. Indeed, GPCRs were detected in distal tubular cells and in the macula densa, suggesting a sensory role in the regulation of the tubuloglomerular feedback by regulating the renin release. A more recent study reported opposite effects of GPCR functions. In this study, the olfactory receptor78 (Olfr78) and the GPR41 knockout mice models were used to determine the role of the SCFA and their receptors in the regulation of renal vascular tone and release of renin. Both Olfr78 and GPR41 were detected in the renal vasculature. However, whereas Olfr 78 knockout mice presented a lower BP associated with a lower plasma level of renin, the opposite was observed in GPR41 knockout mice. That study revealed that Olfr78 activation promotes an increase of BP, whereas the activation of GPR41 contributes to the hypotensive effect of propionate. This opposite effect may act to buffer BP modulation. The role of these receptors in insulin resistance is uncertain. However, SCFAs released in the bloodstream can modulate diverse cellular signaling such as the renal renin–angiotensin system, which may in turn promote the impairment of insulin signaling. Clearly, further investigations are needed to delineate the exact role of these orphan GPCRs.
Curr Opin Nephrol Hypertens. 2015;24(1):28-36. © 2015 Lippincott Williams & Wilkins