Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41)

Abstract

The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis. microbiota | superior cervical ganglion | FFAR3 | probiotics | fasting

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 …”

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