The gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43

Abstract

The gut microbiota affects nutrient acquisition and energy regulation of the host, and can influence the development of obesity, insulin resistance, and diabetes. During feeding, gut microbes produce short-chain fatty acids, which are important energy sources for the host. Here we show that the short-chain fatty acid receptor GPR43 links the metabolic activity of the gut microbiota with host body energy homoeostasis. We demonstrate that GPR43-deficient mice are obese on a normal diet, whereas mice overexpressing GPR43 specifically in adipose tissue remain lean even when fed a high-fat diet. Raised under germ-free conditions or after treatment with antibiotics, both types of mice have a normal phenotype. We further show that short-chain fatty acid-mediated activation of GPR43 suppresses insulin signalling in adipocytes, which inhibits fat accumulation in adipose tissue and promotes the metabolism of unincorporated lipids and glucose in other tissues. These findings establish GPR43 as a sensor for excessive dietary energy, thereby controlling body energy utilization while maintaining metabolic homoeostasis.

Control of appetite and energy intake by SCFA: what are the potential underlying mechanisms?

“…Both FFAR2 and FFAR3 are activated by physiological concentrations of SCFA, although a preference of FFAR2 for acetate and propionate and of FFAR3 for propionate and butyrate has been reported (29)(30)(31) . These receptors have been shown to be expressed not only in the gut epithelium (32,33) where SCFA are produced and are at their highest concentrations, but also at multiple tissue sites, including adipose tissue (34)(35)(36) , immune cells (29) , skeletal muscle (31) and within the peripheral nervous system (37,38) . A possible role for these receptors in energy intake regulation emerged with the identification that FFAR2 and FFAR3 are present on colonic endocrine L-cells (32,33) .…”

“…Furthermore, it was found in vivo that elevating circulating levels of propionate increased leptin levels in mice. Nevertheless, not all researchers have been able to detect FFAR3 in different adipose tissue sites (34,36,37) , thus the role of FFAR3 in adipose tissue function is currently a contentious topic. It has been …”

“…consistently reported that FFAR2 is abundantly expressed in white adipose tissue (34)(35)(36) and suggested that FFAR2 may be responsible for stimulating leptin release from adipocytes. It was found that leptin secretion from wild-type adipocytes was increased by acetate, yet butyrate had no significant effect (35) .…”

Modulatory Effects of Gut Microbiota on the Central Nervous System: How Gut Could Play a Role in Neuropsychiatric Health and Diseases

“…68 SCFAs can act as signaling molecules by binding to G protein-coupled receptors, Gpr41, and Gpr43. [69][70][71] It has been shown that Gpr41 and Gpr43 receptors are abundantly present on the surface of gut epithelial and immune cells and are activated by SCFAs. This activation can provoke an inflammatory and immune response that can be helpful in the setting of an acute infection, but dysregulation can produce an exaggerated response leading to increased gut permeability and increased absorption of neuro-active metabolites.…”

Gut hormones and gut microbiota: implications for kidney function and hypertension

“…38 In addition, via GPR43 activation, SCFAs suppress insulin signaling in adipocytes, thereby improving metabolism, in part, by inhibiting the accumulation of fat in adipose tissue. 39 By contrast, GPR41 increases energy expenditure by stimulating the sympathetic nervous system which could also raise BP. 40 In addition, both Olfr78 and Gpr41 are expressed in smooth muscle cells of small resistance vessels.…”