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Fatty acid oxidation is required for active and quiescent brown adipose tissue maintenance and thermogenic programing.

ABSTRACT: OBJECTIVE:To determine the role of fatty acid oxidation on the cellular, molecular, and physiologic response of brown adipose tissue to disparate paradigms of chronic thermogenic stimulation. METHODS:Mice with an adipose-specific loss of Carnitine Palmitoyltransferase 2 (Cpt2A-/-), that lack mitochondrial long chain fatty acid ?-oxidation, were subjected to environmental and pharmacologic interventions known to promote thermogenic programming in adipose tissue. RESULTS:Chronic administration of ?3-adrenergic (CL-316243) or thyroid hormone (GC-1) agonists induced a loss of BAT morphology and UCP1 expression in Cpt2A-/- mice. Fatty acid oxidation was also required for the browning of white adipose tissue (WAT) and the induction of UCP1 in WAT. In contrast, chronic cold (15 °C) stimulation induced UCP1 and thermogenic programming in both control and Cpt2A-/- adipose tissue albeit to a lesser extent in Cpt2A-/- mice. However, thermoneutral housing also induced the loss of UCP1 and BAT morphology in Cpt2A-/- mice. Therefore, adipose fatty acid oxidation is required for both the acute agonist-induced activation of BAT and the maintenance of quiescent BAT. Consistent with this data, Cpt2A-/- BAT exhibited increased macrophage infiltration, inflammation and fibrosis irrespective of BAT activation. Finally, obese Cpt2A-/- mice housed at thermoneutrality exhibited a loss of interscapular BAT and were refractory to ?3-adrenergic-induced energy expenditure and weight loss. CONCLUSION:Mitochondrial long chain fatty acid ?-oxidation is critical for the maintenance of the brown adipocyte phenotype both during times of activation and quiescence.

SUBMITTER: Gonzalez-Hurtado E

PROVIDER: S-EPMC5784326 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Fatty acid oxidation is required for active and quiescent brown adipose tissue maintenance and thermogenic programing.

Gonzalez-Hurtado Elsie E Lee Jieun J Choi Joseph J Wolfgang Michael J MJ

Molecular metabolism 20171111

<h4>Objective</h4>To determine the role of fatty acid oxidation on the cellular, molecular, and physiologic response of brown adipose tissue to disparate paradigms of chronic thermogenic stimulation.<h4>Methods</h4>Mice with an adipose-specific loss of Carnitine Palmitoyltransferase 2 (Cpt2<sup>A-/-</sup>), that lack mitochondrial long chain fatty acid β-oxidation, were subjected to environmental and pharmacologic interventions known to promote thermogenic programming in adipose tissue.<h4>Resul ...[more]

PMID: 29175051

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Project description:ObjectiveUnderstanding the mechanisms that control brown adipose tissue (BAT) mass and functionality is crucial for our understanding of how the disruption of energy homeostasis leads to obesity. Bernerdinali Seip Congenital Lipodystrophy (BSCL) type 2 (BSCL2, a.k.a. SEIPIN), a lipodystrophy-associated protein, has been shown to not be required for brown adipogenesis, but it has been shown to be essential for perinatal BAT development. However, its role in mature BAT maintenance and thermogenic programing remains poorly understood.MethodsWe subjected Bscl2f/f and Bscl2UCP1-BKO (BKO) mice with a brown adipose-specific loss of BSCL2 through UCP1 promoter-driven Cre to environmental, pharmacological and diet interventions to challenge BAT functionality and reprogramming. We carried out physiological, molecular and transcriptomic analyses of BAT.ResultsThe deletion of BSCL2 in mature brown adipocytes increased sympathetic nervous system-independent cAMP/protein kinase A (PKA) signaling in BAT. Such activation reduced BAT triglyceride content and mass and was sufficient to reduce plasma triglyceride, but not enough to combat thermoneutral and high fat diet-induced obesity. Surprisingly, BKO mice displayed an impaired response to acute and chronic cold challenges despite cAMP/PKA activation. When subjected to chronic cold exposure or the administration of a β3-adrenergic agonist, CL 316,243, BKO mice failed to induce BAT recruitment and underwent dramatic brown adipocyte loss. Transcriptomic analysis revealed pathological BAT remodeling with inflammation and fibrosis, which was further exacerbated by a chronic thermogenic challenge in BKO mice. Mechanistically, we found abnormal mitochondrial shapes and function in BAT of BKO mice housed at 21 °C; as well as mitochondrial DNA depletion and necroptotic-mediated brown adipocyte death after chronic thermogenic insult.ConclusionBSCL2-mediated lipid catabolism within BAT is crucial for mature brown adipocyte function and survival both during times of activation and quiescence. BSCL2 is an important regulator of mature brown adipocyte mitochondrial metabolism, necroptosis and thus adaptive thermogenesis.

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Fatty acid oxidation is required for active and quiescent brown adipose tissue maintenance and thermogenic programing.

Publications

Fatty acid oxidation is required for active and quiescent brown adipose tissue maintenance and thermogenic programing.

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