Dataset Information

Depletion of JunB increases adipocyte thermogenic capacity and ameliorates diet-induced insulin resistance.

ABSTRACT: The coexistence of brown adipocytes with low and high thermogenic activity is a fundamental feature of brown adipose tissue heterogeneity and plasticity. However, the mechanisms that govern thermogenic adipocyte heterogeneity and its significance in obesity and metabolic disease remain poorly understood. Here we show that in male mice, a population of transcription factor jun-B (JunB)-enriched (JunB⁺) adipocytes within the brown adipose tissue exhibits lower thermogenic capacity compared to high-thermogenic adipocytes. The JunB⁺ adipocyte population expands in obesity. Depletion of JunB in adipocytes increases the fraction of adipocytes exhibiting high thermogenic capacity, leading to enhanced basal and cold-induced energy expenditure and protection against diet-induced obesity and insulin resistance. Mechanistically, JunB antagonizes the stimulatory effects of PPARγ coactivator-1α on high-thermogenic adipocyte formation by directly binding to the promoter of oestrogen-related receptor alpha, a PPARγ coactivator-1α downstream effector. Taken together, our study uncovers that JunB shapes thermogenic adipocyte heterogeneity, serving a critical role in maintaining systemic metabolic health.

SUBMITTER: Zhang X

PROVIDER: S-EPMC10954369 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Depletion of JunB increases adipocyte thermogenic capacity and ameliorates diet-induced insulin resistance.

Zhang Xing X Ding Xiaofeng X Wang Chunqing C Le Que Q Wu Dandan D Song Anying A Huang Guixiang G Luo Liping L Luo Yan Y Yang Xin X Goins Aleyah E AE Desai Sharina P SP Qiu Chengrui C Silva Floyd D FD Feldman Lily Elizabeth LE Zhou Jianlin J Spafford Michael F MF Boyd Nathan H NH Prossnitz Eric R ER Yang Xuexian O XO Wang Qiong A QA Liu Meilian M

Nature metabolism 20240108 1

The coexistence of brown adipocytes with low and high thermogenic activity is a fundamental feature of brown adipose tissue heterogeneity and plasticity. However, the mechanisms that govern thermogenic adipocyte heterogeneity and its significance in obesity and metabolic disease remain poorly understood. Here we show that in male mice, a population of transcription factor jun-B (JunB)-enriched (JunB<sup>+</sup>) adipocytes within the brown adipose tissue exhibits lower thermogenic capacity compa ...[more]

PMID: 38191667

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Project description:ObjectiveAdipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is a recently identified LD-associated protein in hepatocytes that promotes hepatic lipid storage, but its role in the adipocyte had not been investigated. Here we tested the hypothesis that Hig2 localization to LDs in adipocytes promotes adipose tissue lipid deposition and systemic glucose homeostasis.MethodWhite and brown adipocyte-deficient (Hig2fl/fl × Adiponection cre+) and selective brown/beige adipocyte-deficient (Hig2fl/fl × Ucp1 cre+) mice were generated to investigate the role of Hig2 in adipose depots. Additionally, we used multiple housing temperatures to investigate the role of active brown/beige adipocytes in this process.ResultsHig2 localized to LDs in SGBS cells, a human adipocyte cell strain. Mice with adipocyte-specific Hig2 deficiency in all adipose depots demonstrated reduced visceral adipose tissue weight and increased glucose tolerance. This metabolic effect could be attributed to brown/beige adipocyte-specific Hig2 deficiency since Hig2fl/fl × Ucp1 cre+ mice displayed the same phenotype. Furthermore, when adipocyte-deficient Hig2 mice were moved to thermoneutral conditions in which non-shivering thermogenesis is deactivated, these improvements were abrogated and glucose intolerance ensued. Adipocyte-specific Hig2 deficient animals displayed no detectable changes in adipocyte lipolysis or energy expenditure, suggesting that Hig2 may not mediate these metabolic effects by restraining lipolysis in adipocytes.ConclusionsWe conclude that Hig2 localizes to LDs in adipocytes, promoting adipose tissue lipid deposition and that its selective deficiency in active brown/beige adipose tissue mediates improved glucose tolerance at 23 °C. Reversal of this phenotype at thermoneutrality in the absence of detectable changes in energy expenditure, adipose mass, or liver triglyceride suggests that Hig2 deficiency triggers a deleterious endocrine or neuroendocrine pathway emanating from brown/beige fat cells.

Dataset Information

Depletion of JunB increases adipocyte thermogenic capacity and ameliorates diet-induced insulin resistance.

Publications

Depletion of JunB increases adipocyte thermogenic capacity and ameliorates diet-induced insulin resistance.

Similar Datasets

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