Supra-pharmacological concentration of capsaicin stimulates brown adipogenesis through induction of endoplasmic reticulum stress

Ryosuke Kida,Masaru Murakami,Osamu Hashimoto,Teruo Kawada,Taiki Noguchi,Tohru Matsui,Masayuki Funaba

doi:10.1038/s41598-018-19223-2

Ryosuke Kida, Masaru Murakami + Show 5 more

Open Access

https://doi.org/10.1038/s41598-018-19223-2

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Abstract

We previously showed that brown (pre)adipocytes express Trpv1, a capsaicin receptor, and that capsaicin stimulates differentiation of brown preadipocytes in the late stages of brown adipogenesis. The present study revealed that treatment with 100 μM capsaicin stimulates brown adipogenesis by inducing endoplasmic reticulum (ER) stress. Treatment with capsaicin (100 μM) during brown adipogenesis enhanced lipid accumulation and the expression of Ucp1, a gene selectively expressed in brown adipocytes. Capsaicin treatment also caused an increase in the cytosolic calcium concentration even when extracellular calcium was removed. I-RTX, a Trpv1 inhibitor, did not modulate the increase in cytosolic calcium concentration, lipid accumulation or Ucp1 expression. Previous studies revealed that the release of calcium from the ER induces ER stress, leading to the conversion of X-box binding protein 1 (Xbp1) pre-mRNA to spliced Xbp1 (sXbp1) as well as the up-regulation of Chop expression. Capsaicin treatment increased the expression of sXbp1 and Chop in brown preadipocytes and did not enhance lipid accumulation or Ucp1 expression in Xbp1 knockdown cells. The present results describe a novel mechanism of brown adipogenesis regulation via ER stress that is induced by a supra-pharmacological concentration of capsaicin.

Highlights

Obesity, defined as an increase in body fat mass, is one of the leading causes of chronic illness and premature death; obesity triggers various diseases such as type 2 diabetes, hypertension and cardiovascular disease[1,2]
We found that X-box binding protein 1 (Xbp1), a gene activated in response to endoplasmic reticulum (ER) stress[21,22], positively regulated brown adipogenesis
We previously revealed that treatment with 0.1 μM capsaicin slightly, but directly, stimulated differentiation of brown preadipocytes during the late stages of brown adipogenesis

Summary

Introduction

Obesity, defined as an increase in body fat mass, is one of the leading causes of chronic illness and premature death; obesity triggers various diseases such as type 2 diabetes, hypertension and cardiovascular disease[1,2]. The ingestion of capsaicin increases energy expenditure and brown adipocyte-mediated thermogenesis[12,13,14,15]. We showed the expression of transient receptor potential vanilloid 1 (Trpv1), a capsaicin receptor[19], in brown adipose tissues and demonstrated that capsaicin slightly, but directly, stimulated differentiation of brown preadipocytes in the late stage of brown adipogenesis[20]. These results prompted us to further explore the role of capsaicin in the regulation of brown adipogenesis. The present study reveals a role for ER stress in stimulating brown preadipocyte differentiation, which shows promise as a potential target of pharmacotherapies for obesity

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