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

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??M capsaicin stimulates brown adipogenesis by inducing endoplasmic reticulum (ER) stress. Treatment with capsaicin (100??M) 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.

SUBMITTER: Kida R

PROVIDER: S-EPMC5770457 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Kida Ryosuke R Noguchi Taiki T Murakami Masaru M Hashimoto Osamu O Kawada Teruo T Matsui Tohru T Funaba Masayuki M

Scientific reports 20180116 1

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 adipocyte ...[more]

PMID: 29339762

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Project description:BackgroundThere is growing evidence that chronic exposure to inorganic arsenic (iAs) is associated with an increased prevalence of type 2 diabetes (T2D). However, the mechanisms for the diabetogenic effect of iAs are still largely unknown. White adipose tissue (WAT) actively stores and releases energy and maintains lipid and glucose homeostasis.ObjectiveWe sought to determine the mechanisms of arsenic suppression of adipogenesis.MethodsThe effects and associated mechanisms of iAs and its major metabolites on adipogenesis were determined in 3T3-L1 preadipocytes, mouse adipose-derived stromal-vascular fraction cells (ADSVFCs), and human adipose tissue-derived stem cells (ADSCs).ResultsExposure of 3T3-L1 preadipocytes to noncytotoxic levels of arsenic, including inorganic arsenite (iAs3+, ? 5 ?M), inorganic arsenate (? 20 ?M), trivalent monomethylated arsenic (MMA3+, ? 1 ?M), and trivalent dimethylated arsenic (DMA3+, ? 2 ?M) decreased adipogenic hormone-induced adipogenesis in a concentration-dependent manner. In addition, iAs3+, MMA3+, and DMA3+ exhibited a strong inhibitory effect on adipogenesis in primary cultured mouse ADSVFCs and human ADSCs. Time-course studies in 3T3-L1 cells revealed that inhibition of adipogenesis by arsenic occurred in the early stage of terminal adipogenic differentiation and was highly correlated with the induction of C/EBP homologous protein (CHOP10), an endoplasmic reticulum (ER) stress response protein. Induction of CHOP10 by arsenic is associated with reduced DNA-binding activity of CCAAT/enhancer-binding protein ? (C/EBP?), which regulates the transcription of peroxisome proliferator-activated receptor ? and C/EBP?.ConclusionsLow-level iAs and MMA3+ trigger the ER stress response and up-regulate CHOP10, which inhibits C/EBP? transcriptional activity, thus suppressing adipogenesis. Arsenic-induced dysfunctional adipogenesis may be associated with a reduced capacity of WAT to store lipids and with insulin resistance.

Project description:Pharmacological activation of the activating transcription factor 6 (ATF6) arm of the Unfolded Protein Response (UPR) has proven useful for ameliorating proteostasis deficiencies in a variety of etiologically diverse diseases. Previous high-throughput screening efforts identified the small molecule AA147 as a potent and selective ATF6 activating compound that operates through a mechanism involving metabolic activation of its 2-amino- p -cresol substructure affording a quinone methide, which then covalently modifies a subset of ER protein disulfide isomerases (PDIs). Intriguingly, another compound identified in this screen, AA132, also contains a 2-amino- p -cresol moiety; however, this compound showed less transcriptional selectivity, instead globally activating all three arms of the UPR. Here, we show that AA132 activates global UPR signaling through a mechanism analogous to that of AA147, involving metabolic activation and covalent PDI modification. Chemoproteomic-enabled analyses show that AA132 covalently modifies PDIs to a greater extent than AA147. Paradoxically, activated AA132 reacts slower with PDIs, indicating it is less reactive than activated AA147. This suggests that the higher labeling of PDIs observed with activated AA132 can be attributed to its lower reactivity, which allows this activated compound to persist longer in the cellular environment prior to quenching by endogenous nucleophiles. Collectively, these results suggest that AA132 globally activates the UPR through increased engagement of ER PDIs. Consistent with this, reducing the cellular concentration of AA132 decreases PDI modifications and allows for selective ATF6 activation. Our results highlight the relationship between metabolically activatable-electrophile stability, ER proteome reactivity, and the transcriptional response observed with the enaminone chemotype of ER proteostasis regulators, enabling continued development of next-generation ATF6 activating compounds.

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

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

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