No abstract

Dysregulation of adipose tissue plasmalogen metabolism is associated with obesity-related metabolic diseases. We report that feeding mice a high-fat diet reduces adipose tissue lysoplasmalogen levels and increases transmembrane protein 86 A (TMEM86A), a putative lysoplasmalogenase. Untargeted lipidomic analysis demonstrates that adipocyte-specific TMEM86A-knockout (AKO) increases lysoplasmalogen content in adipose tissue, including plasmenyl lysophosphatidylethanolamine 18:0 (LPE P-18:0). Surprisingly, TMEM86A AKO increases protein kinase A signalling pathways owing to inhibition of phosphodiesterase 3B and elevation of cyclic adenosine monophosphate. TMEM86A AKO upregulates mitochondrial oxidative metabolism, elevates energy expenditure, and protects mice from metabolic dysfunction induced by high-fat feeding. Importantly, the effects of TMEM86A AKO are largely reproduced in vitro and in vivo by LPE P-18:0 supplementation. LPE P-18:0 levels are significantly lower in adipose tissue of human patients with obesity, suggesting that TMEM86A inhibition or lysoplasmalogen supplementation might be therapeutic approaches for preventing or treating obesity-related metabolic diseases.

Cell death-inducing DNA fragmentation factor-like effector A (CIDEA) is a lipid droplet-associated protein and is a known marker of the thermogenic capacity of brown/beige adipocytes. To monitor the expression of CIDEA in live mice in a non-invasive manner, we generated CIDEA reporter mice expressing multicistronic mRNAs encoding CIDEA, luciferase 2, and tdTomato proteins under the control of the Cidea promoter. The expression level of endogenous CIDEA protein in adipose tissue was not affected by the expression of polycistronic reporters. The two CIDEA reporters, luciferase 2 and tdTomato, correctly reflected CIDEA protein levels. Importantly, luciferase activity was induced by cold exposure and the treatment with β3-adrenergic receptor agonist CL316,243 in interscapular and inguinal adipose tissue, which was detectable by in vivo bioluminescence imaging. We further evaluated the effects of candidate brown adipogenic agents using this CIDEA reporter system and demonstrated a positive correlation between drug-induced luciferase activity and thermogenic gene expression levels both in vitro and in vivo. Collectively, we established a dual CIDEA reporter mouse model in which fluorescence and luminescence signals correctly reflect CIDEA expression, and therefore, suggested that this reporter system can be used to evaluate the thermogenic efficacy of candidate molecules.

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The high incidence of obesity has increased the need to discover new therapeutic targets to combat obesity and obesity-related metabolic diseases. Obesity is defined as an abnormal accumulation of adipose tissue, which is one of the major metabolic organs that regulate energy homeostasis. However, there are currently no approved anti-obesity therapeutics that directly target adipose tissue metabolism. With recent advances in the understanding of adipose tissue biology, molecular mechanisms involved in brown adipose tissue expansion and metabolic activation have been investigated as potential therapeutic targets to increase energy expenditure. This review focuses on G-protein coupled receptors (GPCRs) as they are the most successful class of druggable targets in human diseases and have an important role in regulating adipose tissue metabolism. We summarize recent findings on the major GPCR classes that regulate thermogenesis and mitochondrial metabolism in adipose tissue. Improved understanding of GPCR signaling pathways that regulate these processes could facilitate the development of novel pharmacological approaches to treat obesity and related metabolic disorders.