Adipocyte-expressed SIRT3 manipulates carnitine pool to orchestrate metabolic reprogramming and polarization of macrophages.

Obesity is accompanied with accumulation and pro-inflammatory polarization of macrophages in adipose tissue (AT), leading to systematical inflammation and insulin resistance. Impaired lipid metabolism and endocrine function in adipocytes is recognized as a culprit in the onset of adipose tissue inflammation. Lipid levels can be managed via inhibiting both synthesis and transport or via increasing fatty acid oxidation (FAO). The deacetylase Sirtuin 3 (SIRT3) participates in inflammatory responses via regulating mitochondrial function and FAO. Herein, an AT-specific SIRT3 overexpression mice model (AT-SIRT3OE) was generated using adeno-associated virus transduction. AT-specific SIRT3 overexpression did not alter body weight or adiposity in either regular chow diet or high-fat diet (HFD) fed mice. AT-SIRT3OE mice exhibited improved insulin sensitivity in HFD-fed mice, through alleviating infiltration of macrophage and pro-inflammatory macrophage polarization in the epididymal AT. The metabolomics analysis indicated that SIRT3 overexpressed adipocytes accumulated more L-carnitine (LC) and less long-chain acylarnitines in the medium. Furthermore, SIRT3 directly deacetylates and activates carnitine palmitoyltransferase 2 (CPT2), an obligate step in mitochondrial long-chain FAO, to enhance the LC turnover pool in adipocytes, which in turn promoted lipid metabolism and anti-inflammatory polarization in macrophages. Collectively, our study provided new evidence that adipocyte-expressed SIRT3 alleviates inflammatory crosstalk between adipocytes and macrophages through manipulating LC pool. Activating SIRT3 in adipocytes could be a potential strategy to alleviate obesity-related metabolic diseases.