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. 2004 Jan 27;101(4):1045-50.
doi: 10.1073/pnas.2637002100. Epub 2004 Jan 13.

Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41 (V体育官网入口)

Yumei Xiong  1 , Norimasa Miyamoto, Kenji Shibata, Mark A Valasek, Toshiyuki Motoike, Rafal M Kedzierski, Masashi Yanagisawa
Affiliations

Short-chain fatty acids stimulate leptin production in adipocytes through the G protein-coupled receptor GPR41

Yumei Xiong et al. Proc Natl Acad Sci U S A. .

Abstract

Leptin is an adipose-derived hormone that regulates a wide variety of physiological processes, including feeding behavior, metabolic rate, sympathetic nerve activity, reproduction, and immune response. Circulating leptin levels are tightly regulated according to energy homeostasis in vivo. Although mechanisms for the regulation of leptin production in adipocytes are not well understood, G protein-coupled receptors may play an important role in this adipocyte function. Here we report that C2-C6 short-chain fatty acids, ligands of an orphan G protein-coupled receptor GPR41, stimulate leptin expression in both a mouse adipocyte cell line and mouse adipose tissue in primary culture. Acute oral administration of propionate increases circulating leptin levels in mice. The concentrations of short-chain fatty acids required to stimulate leptin production are within physiological ranges, suggesting the relevance of this pathway in vivo. VSports手机版.

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Figures

Fig. 1.
Fig. 1.
SCFAs activate GPR41. (A) Dose–response curves of C2–C6 straightchain fatty acids in stimulating pigment aggregation in Xenopus melanophore cells transfected with human GPR41 cDNA. (B) Dose–response curves of C4–C6 branched-chain fatty acids in stimulating pigment aggregation. (C) Reduction of cAMP levels in response to SCFA in CHO-K1 cells expressing GPR41. *, P < 0.01 compared with cells treated with forskolin only. Experiments were performed in quadruplicate in A and B and triplicate in C. Error bars represent SEM.
Fig. 2.
Fig. 2.
SCFAs stimulate leptin production in adipocytes. (A) RT-PCR analysis demonstrating expression of mouse GPR41 mRNA in white adipose tissue and Ob-Luc cells: from left to right, brown adipose tissue (BAT), undifferentiated Ob-Luc cells, differentiated Ob-Luc cells, white adipose tissue (WAT). (B) Dose–response curves of C2–C5 SCFAs in stimulating the leptin locus in Ob-Luc cells. Luciferase activity was presented as luminescent light units. (C) Dose–response curves of propionic acid in stimulating the leptin locus in Ob-Luc cells infected with control virus or virus containing mouse GPR41 cDNA. (D) Dose–response curves of propionic acid in stimulating the leptin locus in Ob-Luc cells infected with virus containing unrelated control sequence or virus supernatants containing siRNA sequences targeting three different regions of GPR41 cDNA. (E) Dose–response curves of SCFAs in increasing leptin produced from mouse adipose tissues in primary culture. Experiments were performed in quadruplicate in B and with n = 6 in C–E. Error bars represent SEM.
Fig. 3.
Fig. 3.
Stimulatory effect of propionate in adipocytes is mediated by the Gi pathway. (A) Stimulation of the leptin locus by propionic acid in Ob-Luc cells pretreated with or without pertussis toxin. *, P < 0.01 compared with baseline. (B) Response of native mouse adipose tissues to propionic acid after treatment with or without pertussis toxin. *, P < 0.01 compared with baseline. (C) Inhibition of isoproterenol-induced cAMP accumulation by SCFAs in adipocytes. *, P < 0.01 compared with cells treated with forskolin only. Experiments were performed in quadruplicate. Error bars represent SEM.
Fig. 4.
Fig. 4.
Stimulatory effect of propionic acid on leptin production is modulated by adenosine and insulin. (A) Leptin levels in conditioned medium from mouse adipose tissue cultures treated with propionic acid or insulin in the presence or absence of adenosine deaminase. *, P < 0.05 compared to corresponding experiments without adenosine deaminase treatment. #, P < 0.01 compared to corresponding experiments without treatment of propionic acid or insulin. (B) Leptin levels in conditioned medium from mouse adipose tissue cultures in the presence of propionic acid, insulin, or both together. *, P < 0.01 compared with baseline. #, P < 0.01 compared with cultures treated with propionic acid or insulin alone. Experiments were performed in quadruplicate. Error bars represent SEM.
Fig. 5.
Fig. 5.
Acute oral administration of propionate in mice increases circulating leptin levels. (A) Plasma leptin levels in mice administered with sodium propionate or control sodium chloride solutions (n = 9 per group). *, P < 0.05 compared with control group. (B) Plasma leptin levels normalized to epididymal fat mass in mice administered with sodium propionate or sodium chloride solutions. *, P < 0.01 compared with control group. (C) Plasma leptin levels in mice administered with neutral sodium hexanoate or control sodium chloride solutions (n = 6 per group). (D) Plasma leptin levels normalized to epididymal fat mass in mice administered with sodium hexanoate or sodium chloride solutions. Error bars represent SEM.
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