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STAT5 is required for lipid breakdown and beta-adrenergic responsiveness of brown adipose tissue.

ABSTRACT: Objective:Increasing energy expenditure through activation of brown adipose tissue (BAT) thermogenesis is an attractive approach to counteract obesity. It is therefore essential to understand the molecular mechanisms that control BAT functions. Until now several members of the Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway have been implicated as being relevant for BAT physiology. However, whether the STAT family member STAT5 is important for the thermogenic property of adipose tissues is unknown. Therefore, we have investigated the role of STAT5 in thermogenic fat in this paper.

Methods:We performed metabolic and molecular analyses using mice that harbor an adipocyte-specific deletion of Stat5a/b alleles.

Results:We found that STAT5 is necessary for acute cold-induced temperature maintenance and the induction of lipid mobilization in BAT following ?₃-adrenergic stimulation. Moreover, mitochondrial respiration of primary differentiated brown adipocytes lacking STAT5 was diminished. Increased sensitivity to cold stress upon STAT5 deficiency was associated with reduced expression of thermogenic markers including uncoupling protein 1 (UCP1), while decreased stimulated lipolysis was linked to decreased protein kinase A (PKA) activity. Additionally, brown remodeling of white adipose tissue was diminished following chronic ?₃-adrenergic stimulation, which was accompanied by a decrease in mitochondrial performance.

Conclusion:We conclude that STAT5 is essential for the functionality and the ?-adrenergic responsiveness of thermogenic adipose tissue.

SUBMITTER: Kaltenecker D

PROVIDER: S-EPMC7322099 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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STAT5 is required for lipid breakdown and beta-adrenergic responsiveness of brown adipose tissue.

Kaltenecker Doris D Spirk Katrin K Ruge Frank F Grebien Florian F Herling Marco M Rupprecht Anne A Kenner Lukas L Pohl Elena E EE Mueller Kristina M KM Moriggl Richard R

Molecular metabolism 20200528

<h4>Objective</h4>Increasing energy expenditure through activation of brown adipose tissue (BAT) thermogenesis is an attractive approach to counteract obesity. It is therefore essential to understand the molecular mechanisms that control BAT functions. Until now several members of the Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway have been implicated as being relevant for BAT physiology. However, whether the STAT family member STAT5 is important for the the ...[more]

PMID: 32473405

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Project description:ObjectiveT-box 1 (TBX1) has been identified as a genetic marker of beige adipose tissue. TBX1 is a mesodermal development transcription factor essential for tissue patterning and cell fate determination. However, whether it plays a role in the process of adipose beiging or how it functions in adipose tissue has not been reported. Here, we examined the function of TBX1 in adipose tissue as well as adipose-derived stem cells from mice and humans.MethodsAdipose-specific TBX1 transgenic (TBX1 AdipoTG) and adipose-specific TBX1 knockout (TBX1 AdipoKO) mice were generated to explore the function of TBX1 in the process of adipose beiging, metabolism and energy homeostasis in vivo. In vitro, we utilized a siRNA mediated approach to determine the function of TBX1 during adipogenesis in mouse and human stem cells.ResultsAdipose-specific overexpression of TBX1 was not sufficient to fully induce beiging and prevent diet-induced obesity. However, adipose TBX1 expression was necessary to defend body temperature during cold through regulation of UCP1 and for maintaining β3-adrenergic sensitivity and glucose homeostasis in vivo. Loss of adipose TBX1 expression enhanced basal lipolysis and reduced the size of subcutaneous iWAT adipocytes. Reduction of TBX1 expression via siRNA significantly impaired adipogenesis of mouse stromal vascular cells but significantly enhanced adipogenesis in human adipose derived stem cells.ConclusionsAdipose expression of TBX1 is necessary, but not sufficient, to defend body temperature during cold via proper UCP1 expression. Adipose TBX1 expression was also required for proper insulin signaling in subcutaneous adipose as well as for maintaining β-adrenergic sensitivity, but overexpression of TBX1 was not sufficient to induce adipocyte beiging or to prevent diet-induced obesity. TBX1 expression is enriched in adipose stem cells in which it has contrasting effects on adipogenesis in mouse versus human cells. Collectively, these data demonstrate the importance of adipose TBX1 in the regulation of beige adipocyte function, energy homeostasis, and adipocyte development.

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STAT5 is required for lipid breakdown and beta-adrenergic responsiveness of brown adipose tissue.

Publications

STAT5 is required for lipid breakdown and beta-adrenergic responsiveness of brown adipose tissue.

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