What activates thermogenesis when lipid droplet lipolysis is absent in brown adipocytes?

Shin, Hyunsu; Shi, Hang; Xue, Bingzhong; Yu, Liqing

doi:10.1080/21623945.2018.1453769

Cited by 19 publications

(21 citation statements)

References 45 publications

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“…Moreover, mice treated with Atglistatin display higher UCP1 levels in adipose tissue (Schweiger et al 2017). Similarly, deletion of CGI-58 in brown adipose tissue, which partially blocks lipolysis, does not block energy dissipation by adipocytes in mice fed ad libitum (Shin et al 2017(Shin et al , 2018. Mice deficient for ERK3 show about 50% reduced Atgl expression, and at the same time, increased Ucp1 expression in white as well as in brown adipose tissue when fed HFD.…”

Section: Discussionmentioning

confidence: 98%

The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation

et al. 2020

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Obesity-induced diabetes affects >400 million people worldwide. Uncontrolled lipolysis (free fatty acid release from adipocytes) can contribute to diabetes and obesity. To identify future therapeutic avenues targeting this pathway, we performed a high-throughput screen and identified the extracellular-regulated kinase 3 (ERK3) as a hit. We demonstrated that β-adrenergic stimulation stabilizes ERK3, leading to the formation of a complex with the cofactor MAP kinase-activated protein kinase 5 (MK5), thereby driving lipolysis. Mechanistically, we identified a downstream target of the ERK3/MK5 pathway, the transcription factor FOXO1, which promotes the expression of the major lipolytic enzyme ATGL. Finally, we provide evidence that targeted deletion of ERK3 in mouse adipocytes inhibits lipolysis, but elevates energy dissipation, promoting lean phenotype and ameliorating diabetes. Thus, ERK3/MK5 represents a previously unrecognized signaling axis in adipose tissue and an attractive target for future therapies aiming to combat obesity-induced diabetes.These authors contributed equally to this work. Corresponding author: grzegorz.sumara@uni-wuerzburg.de Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.

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Section: Discussionmentioning

confidence: 98%

The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation

et al. 2020

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“…The presence of smaller lipid droplets in the BAT from mice lacking HuR is interesting and suggestive of a possible fuel shortage mechanism in BAT from Adipo-HuR −/mice. However, it has been shown that lipolysis of lipid droplets within BAT is not required for thermogenesis [34] and, more recently, that lipid droplets within BAT are entirely dispensable for cold-induced thermogenesis [35].…”

Section: Discussionmentioning

confidence: 99%

HuR expression in adipose tissue mediates energy expenditure and acute thermogenesis independent of UCP1 expression

et al. 2020

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The goal of this study was to define the functional role of adipocyte-specific expression of the RNA binding protein Human antigen R (HuR). Mice with an adipocyte-specific deletion of HuR (Adipo-HuR −/-) were generated by crossing HuR floxed (HuR fl/fl) mice with mice expressing adiponectin-driven cre-recombinase (Adipoq-cre). Our results show that Adipo-HuR −/mice display a lean phenotype compared to wild-type littermate controls. HuR deletion results in a diet-independent reduction in percent body fat composition along with an increase in energy expenditure. Functionally, Adipo-HuR −/mice show a significant impairment in acute adaptive thermogenesis (six hours at 4°C), but uncoupling protein 1 (UCP1) protein expression in brown adipose tissue (BAT) is unchanged compared to control. Pharmacological inhibition of HuR also results in a marked decline in core body temperature following acute cold challenge independent of UCP1 protein expression. Among the 588 HuR-dependent genes in BAT identified by RNA-seq analysis, gene ontology analysis shows a significant enrichment in mediators of calcium transport and signalling, almost all of which are decreased in Adipo-HuR −/mice compared to control. In conclusion, adipocyte expression of HuR plays a central role in metabolic homoeostasis and mediates UCP1-independent thermogenesis in BAT, potentially through post-transcriptional control of intracellular calcium transport.

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“…Several studies demonstrate that food consumption could compensate for thermogenic fuel depletion during cold exposure (40,41), especially during the light phase (11,42). Thus, to avoid any confounding effect of feeding, mice were housed at 4°C for 1 wk with ad libitum access to food, then maintained in the cold environment under fasting conditions for 6 h, beginning at ZT1.…”

Section: Fatty Acid Oxidationmentioning

confidence: 99%

Circadian lipid synthesis in brown fat maintains murine body temperature during chronic cold

Adlanmérini

Carpenter

Remsberg

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Ambient temperature influences the molecular clock and lipid metabolism, but the impact of chronic cold exposure on circadian lipid metabolism in thermogenic brown adipose tissue (BAT) has not been studied. Here we show that during chronic cold exposure (1 wk at 4 °C), genes controlling de novo lipogenesis (DNL) includingSrebp1, the master transcriptional regulator of DNL, acquired high-amplitude circadian rhythms in thermogenic BAT. These conditions activated mechanistic target of rapamycin 1 (mTORC1), an inducer ofSrebp1expression, and engaged circadian transcriptional repressors REV-ERBα and β as rhythmic regulators ofSrebp1in BAT. SREBP was required in BAT for the thermogenic response to norepinephrine, and depletion of SREBP prevented maintenance of body temperature both during circadian cycles as well as during fasting of chronically cold mice. By contrast, deletion of REV-ERBα and β in BAT allowed mice to maintain their body temperature in chronic cold. Thus, the environmental challenge of prolonged noncircadian exposure to cold temperature induces circadian induction of SREBP1 that drives fuel synthesis in BAT and is necessary to maintain circadian body temperature during chronic cold exposure. The requirement for BAT fatty acid synthesis has broad implications for adaptation to cold.

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What activates thermogenesis when lipid droplet lipolysis is absent in brown adipocytes?

Cited by 19 publications

References 45 publications

The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation

The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation

HuR expression in adipose tissue mediates energy expenditure and acute thermogenesis independent of UCP1 expression

Circadian lipid synthesis in brown fat maintains murine body temperature during chronic cold

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