Targeted Disruption of the SUCNR1 Metabolic Receptor Leads to Dichotomous Effects on Obesity

Abstract

A number of metabolites have signaling properties by acting through G-protein-coupled receptors. Succinate, a Krebs cycle intermediate, increases after dysregulated energy metabolism and can bind to its cognate receptor succinate receptor 1 (Sucnr1, or GPR91) to activate downstream signaling pathways. We show that Sucnr1 is highly expressed in the white adipose tissue (WAT) compartment of mice and regulates adipose mass and glucose homeostasis. Sucnr1 2/2 mice were generated, and weight gain was monitored under basal and nutritional stress (high-fat diet [HFD]) conditions. On chow diet, Sucnr1 2/2 mice had increased energy expenditure, were lean with a smaller WAT compartment, and had improved glucose buffering. Lipolysis measurements revealed that Sucnr1 2/2 mice were released from succinate-induced inhibition of lipolysis, demonstrating a function of Sucnr1 in adipose tissue. Sucnr1 deletion also protected mice from obesity on HFD, but only during the initial period; at later stages, body weight of HFD-fed Sucnr1 2/2 mice was almost comparable with wild-type (WT) mice, but WAT content was greater. Also, these mice became progressively hyperglycemic and failed to secrete insulin, although pancreas architecture was similar to WT mice. These findings suggest that Sucnr1 is a sensor for dietary energy and raise the interesting possibility that protocols to modulate Sucnr1 might have therapeutic utility in the setting of obesity.

Involvement of the metabolic sensor GPR81 in cardiovascular control

“…Thus, succinate, which is increased in the situation of ischemia (50), has been reported to inhibit adipose tissue lipolysis via Gi-coupled signalling suppression of cAMP (51) and has a hypertensive effect that is dependent on GPR91 (52). In addition, the local tissue expression of GPR91 in the kidney also has some similarity to GPR81, particularly its expression in the afferent arteriole (53)(54)(55).…”

Succinate causes α-SMA production through GPR91 activation in hepatic stellate cells

“…In dendritic cells, succinate triggers GPR91 activation, which is involved in helper T-cell activation and proinflammatory cytokine production [13]. GPR91 has been found in several highly vascularized tissues, including kidney, heart, liver, white adipose tissue, and retina [6,14,15].…”

Insight into SUCNR1 (GPR91) structure and function

“…In KO mice, the overall content of WAT was increased and concomitant with a hyperglycemic profile, characterized by a reduced insulin secretion. According to McCreath et al, these results point to a role for SUCNR1 in metabolism and metabolic disease in the context of obesity (McCreath et al, 2015).…”

“…SUCNR1 is expressed at the surface of adipocytes of the white adipose tissue (WAT) and stimulation of G; by succinate in these cells inhibits lipolysis and prevents the release of free fatty acids (Fig. 3) (McCreath et al, 2015;Regard, Sato, & Coughlin, 2008).…”

“…Deep metabolic studies have recently demonstrated that Sucnr1 -/-mice have a modified weight gain and glucose homeostasis (McCreath et al, 2015). Mice fed with standard diet displayed a mild lean pheno-type.…”