Let's burn whatever you have: mitofusin 2 metabolically re‐wires brown adipose tissue

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Abstract

Brown adipose tissue (BAT) has received enormous scientific and lay attention in the recent past as its thermogenic, energy‐consuming capacities represent prime candidates for therapeutic interventions toward obesity, glucose intolerance, and diabetes even in humans. The overall positive effects of BAT activation and recruitment on systemic energy homeostasis have been largely attributed to the inherent ability of brown adipocytes to combust fatty acid and glucose energy substrates through mitochondrial uncoupling, driven by the unique expression of uncoupling protein 1 (UCP1). Two recent reports by Boutant et al and Mahdaviani et al now identify the GTPase mitofusin (Mfn) 2 as a key determinant of BAT thermogenic function that is largely independent of its previously described role in mitochondrial fusion [1,2].

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Mitochondrial Patch Clamp of Beige Adipocytes Reveals UCP1-Positive and UCP1-Negative Cells Both Exhibiting Futile Creatine Cycling.

Ambre Bertholet, Lawrence Kazak, Edward Chouchani … (2017)

Cold and other environmental factors induce "browning" of white fat depots-development of beige adipocytes with morphological and functional resemblance to brown fat. Similar to brown fat, beige adipocytes are assumed to express mitochondrial uncoupling protein 1 (UCP1) and are thermogenic due to the UCP1-mediated H(+) leak across the inner mitochondrial membrane. However, this assumption has never been tested directly. Herein we patch clamped the inner mitochondrial membrane of beige and brown fat to provide a direct comparison of their thermogenic H(+) leak (IH). All inguinal beige adipocytes had robust UCP1-dependent IH comparable to brown fat, but it was about three times less sensitive to purine nucleotide inhibition. Strikingly, only ∼15% of epididymal beige adipocytes had IH, while in the rest UCP1-dependent IH was undetectable. Despite the absence of UCP1 in the majority of epididymal beige adipocytes, these cells employ prominent creatine cycling as a UCP1-independent thermogenic mechanism.

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Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice.

Gabriele Schoiswohl, Maja Stefanovic-Racic, Marie Menke … (2015)

Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis in vivo, we generated mice with adipocyte-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme catalyzing triacylglycerol hydrolysis. In contrast to previous models, adiponectin-driven Cre expression was used for targeted ATGL deletion. The resulting adipocyte-specific ATGL knockout (AAKO) mice were then characterized for metabolic and immune phenotypes. Lean and diet-induced obese AAKO mice had reduced adipocyte lipolysis, serum lipids, systemic lipid oxidation, and expression of peroxisome proliferator-activated receptor alpha target genes in adipose tissue (AT) and liver. These changes did not increase overall body weight or fat mass in AAKO mice by 24 weeks of age, in part due to reduced expression of genes involved in lipid uptake, synthesis, and adipogenesis. Systemic glucose and insulin tolerance were improved in AAKO mice, primarily due to enhanced hepatic insulin signaling, which was accompanied by marked reduction in diet-induced hepatic steatosis as well as hepatic immune cell infiltration and activation. In contrast, although adipocyte ATGL deletion reduced AT immune cell infiltration in response to an acute lipolytic stimulus, it was not sufficient to ameliorate, and may even exacerbate, chronic inflammatory changes that occur in AT in response to diet-induced obesity.

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New powers of brown fat: fighting the metabolic syndrome.

Jan Nedergaard, Tore Bengtsson, Barbara Cannon (2011)

An understanding of the full powers of brown adipose tissue (BAT) is only successively being accumulated. In a paper in Nature Medicine, Bartelt et al. (2011) add further impressive aspects to the potential powers of BAT in the combat against the metabolic syndrome by demonstrating its vast capacity for triglyceride clearance and glucose disposal. Copyright © 2011 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Title: EMBO reports

Abbreviated Title: EMBO Rep

Publisher: EMBO

ISSN (Print): 1469-221X

ISSN (Electronic): 1469-3178

Publication date Created: May 23 2017

Publication date Created: July 2017

Publication date (Electronic): May 24 2017

Publication date (Print): July 2017

Volume: 18

Issue: 7

Pages: 1039-1040

Affiliations

[1 ]Institute for Diabetes and Cancer (IDC) Helmholtz Center Munich, and Joint Heidelberg‐IDC Translational Diabetes Program Inner Medicine I Heidelberg University Hospital Heidelberg Germany

[2 ]Chair Molecular Metabolic Control Technical University Munich Munich Germany