The good and bad of adipose tissue macrophage exosomes in obesity

Adipose tissue macrophages regulate adipose tissue inflammation and systemic insulin-glucose homeostasis. In a recent study by Ying et al., 2021Ying W. Gao H. Dos Reis F.C.G. Bandyopadhyay G. Ofrecio J.M. Luo Z. Ji Y. Jin Z. Ly C. Olefsky J.M. MiR-690, an exosomal-derived miRNA from M2-polarized macrophages, improves insulin sensitivity in obese mice.Cell Metab. 2021; 33 (this issue): 781-790Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, M2 polarized bone marrow-derived macrophages secreted exosomes containing miR-690 that, when administered to obese mice, improved glucose-insulin homeostasis. miR-690 reduced expression of Nadk, which decreased inflammation and improved insulin signaling. Adipose tissue macrophages regulate adipose tissue inflammation and systemic insulin-glucose homeostasis. In a recent study by Ying et al., 2021Ying W. Gao H. Dos Reis F.C.G. Bandyopadhyay G. Ofrecio J.M. Luo Z. Ji Y. Jin Z. Ly C. Olefsky J.M. MiR-690, an exosomal-derived miRNA from M2-polarized macrophages, improves insulin sensitivity in obese mice.Cell Metab. 2021; 33 (this issue): 781-790Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, M2 polarized bone marrow-derived macrophages secreted exosomes containing miR-690 that, when administered to obese mice, improved glucose-insulin homeostasis. miR-690 reduced expression of Nadk, which decreased inflammation and improved insulin signaling. Obesity is a major risk factor for the development of insulin resistance that promotes the development of type 2 diabetes mellitus (T2DM). Chronic low-grade inflammation is thought to promote the alterations in insulin-glucose homeostasis associated with obesity (Saltiel and Olefsky, 2017Saltiel A.R. Olefsky J.M. Inflammatory mechanisms linking obesity and metabolic disease.J. Clin. Invest. 2017; 127: 1-4Crossref PubMed Scopus (709) Google Scholar). An important initial observation was that increased levels of inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, in adipose tissue of obese mice and humans were found to contribute to insulin resistance (Fried et al., 1998Fried S.K. Bunkin D.A. Greenberg A.S. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.J. Clin. Endocrinol. Metab. 1998; 83: 847-850Crossref PubMed Scopus (1392) Google Scholar; Hotamisligil et al., 1993Hotamisligil G.S. Shargill N.S. Spiegelman B.M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance.Science. 1993; 259: 87-91Crossref PubMed Scopus (5876) Google Scholar; Perry et al., 2015Perry R.J. Camporez J.G. Kursawe R. Titchenell P.M. Zhang D. Perry C.J. Jurczak M.J. Abudukadier A. Han M.S. Zhang X.M. et al.Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes.Cell. 2015; 160: 745-758Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar). Subsequently, it was observed that an influx of proinflammatory macrophages into adipose tissue was a significant contributor to adipose tissue and obesity-associated insulin resistance (Lumeng et al., 2007Lumeng C.N. Deyoung S.M. Bodzin J.L. Saltiel A.R. Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity.Diabetes. 2007; 56: 16-23Crossref PubMed Scopus (737) Google Scholar; Weisberg et al., 2003Weisberg S.P. McCann D. Desai M. Rosenbaum M. Leibel R.L. Ferrante Jr., A.W. Obesity is associated with macrophage accumulation in adipose tissue.J. Clin. Invest. 2003; 112: 1796-1808Crossref PubMed Scopus (7054) Google Scholar). More recently, a new mechanistic pathway involving secretion of exosomes by adipose tissue macrophages (ATMs) was found to regulate metabolic and inflammatory interactions between adipocytes and macrophages as well as distal tissues (Ying et al., 2017Ying W. Riopel M. Bandyopadhyay G. Dong Y. Birmingham A. Seo J.B. Ofrecio J.M. Wollam J. Hernandez-Carretero A. Fu W. et al.Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity.Cell. 2017; 171: 372-384.e12Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar). Exosomes are small (50–200 nm) extracellular vesicles surrounded by a phospholipid bilayer that carries the molecular components of one cell to another. As such, exosomes can transmit a broad range of molecular signals through exchange of lipids, proteins, and nucleic acids. For example, adipocytes have been found to secrete lipid-laden exosomes expressing the lipid droplet-associated protein perilipin1, phospholipids, neutral lipids, and free cholesterol that are taken up by ATMs and can induce differentiation of bone marrow-derived precursor cells into ATM-like cells (Flaherty et al., 2019Flaherty 3rd, S.E. Grijalva A. Xu X. Ables E. Nomani A. Ferrante Jr., A.W. A lipase-independent pathway of lipid release and immune modulation by adipocytes.Science. 2019; 363: 989-993Crossref PubMed Scopus (141) Google Scholar). Recently, exosomes have been found to carry both mRNA and microRNAs (miRNAs) that can modify gene expression of the recipient cells, which has increased interest in the effects of exosomes in metabolic disorders. miRNAs are expressed first as a single strand of RNA, called pre-miRNA (or pri-miRNA), that anneals to itself and is then cleaved by Dicer, which results in double-stranded RNA (O’Brien et al., 2018O’Brien J. Hayder H. Zayed Y. Peng C. Overview of microRNA biogenesis, mechanisms of actions, and circulation.Front. Endocrinol. (Lausanne). 2018; 9: 402Crossref PubMed Scopus (1134) Google Scholar). The double-stranded RNA is separated by argonaute to produce a mature miRNA-argonaute complex. The binding of the miRNA to argonaute allows it to be trafficked the endosome where it can be packaged within exosomes that make up the multi-vesicular body (MVB) (Siomi and Siomi, 2009Siomi H. Siomi M.C. RISC hitches onto endosome trafficking.Nat. Cell Biol. 2009; 11: 1049-1051Crossref PubMed Scopus (37) Google Scholar) (Figure 1). The MVB can then fuse with the cytoplasmic membrane to release the exosomes. In the obese state, macrophages within adipose tissue, liver, and skeletal muscle promote insulin resistance. Macrophages can be classified based upon their inflammatory phenotype; namely, in obesity the ATMs are predominantly pro-inflammatory, M1-like macrophages, whereas in lean individuals adipose tissue contains anti-inflammatory, M2-like macrophages. Interestingly, Ying et al. made the novel observation that ATMs taken from obese mice on a high-fat diet (HFD) produced exosomes that contained increased levels of miR-155. The exosomes were isolated and injected into lean mice, which increased insulin resistance and localized in adipose tissue, liver, and muscle (Ying et al., 2017Ying W. Riopel M. Bandyopadhyay G. Dong Y. Birmingham A. Seo J.B. Ofrecio J.M. Wollam J. Hernandez-Carretero A. Fu W. et al.Adipose tissue macrophage-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity.Cell. 2017; 171: 372-384.e12Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar). Mice with miR-155 knockout were significantly more sensitive to insulin when on an HFD, even in the absence of body weight changes. Building upon these studies, in this issue of Cell Metabolism, Ying et al. treated bone marrow-derived macrophages (BMDMs) with IL-4 and IL-13 to generate M2 BMDMs and then isolated the secreted exosomes (Ying et al., 2021Ying W. Gao H. Dos Reis F.C.G. Bandyopadhyay G. Ofrecio J.M. Luo Z. Ji Y. Jin Z. Ly C. Olefsky J.M. MiR-690, an exosomal-derived miRNA from M2-polarized macrophages, improves insulin sensitivity in obese mice.Cell Metab. 2021; 33 (this issue): 781-790Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). Notably, injection of the secreted exosomes from M2 macrophages into obese mice improved insulin-glucose homeostasis without affecting adiposity. In vitro studies confirmed that the exosomes were taken up and improved insulin action in 3T3-L1 adipocytes, L6 myocytes, and isolated mouse hepatocytes. To confirm that miRNAs were causing the insulin sensitivity, they used mice with a knockout of Dicer, which eliminated all miRNAs from the exosomes produced by the M2 BMDMs, and as a result these exosomes failed to improve insulin resistance when injected in obese mice. The authors demonstrated that the M2 BMDM-derived exosomes contained high levels of miR-690 and, when the exosomes were injected, this miRNA was taken up in the relevant metabolic tissues. To more precisely confirm the role of miR-690, Ying et al. generated an miR-690 “mimic” that was mixed with Invivofectamine and injected into obese mice. The miR-690 mimic localized in adipose tissue, liver, and skeletal muscle, where it improved insulin-glucose homeostasis. Using the TargetScan 7.2 algorithms to predict mRNA targets of miR-690, as well as several in vitro experiments, the researchers demonstrated that the 3′ UTR of the gene Nadk is a target of miR-690. Nadk is a gene that encodes an NAD+ kinase. To confirm a potential role for Nadk in insulin action, the authors used siRNA against Nadk to reduce its expression in 3T3-L1 adipocytes and mouse hepatocytes and found that knockdown improved insulin action. These exciting observations that macrophage exosomes regulate tissue and systemic insulin-glucose homeostasis, and specifically that miR-690 acts as an insulin sensitizer, raise several important questions. One question that arises is whether macrophages in liver, adipose tissue, and skeletal muscle all express the same miRNAs in exosomes, or if ATM exosomes and their associated miRNAs specifically circulated to liver and skeletal muscle to alter tissue specific and systemic metabolism. Additionally, are there other miRNAs in exosomes from macrophages that are yet to be identified that have important metabolic roles? How is the expression of other genes effected by miR-155 and miR-690 and do the exosome exert cell- and tissue-specific actions? Furthermore, the mechanistic pathway for how Nadk regulates insulin resistance is unknown. Nadk phosphorylates NAD+ to generate NADP+, which is further reduced to NADPH for reductive anabolism. Insulin can stimulate the phosphorylation of Nadk, activating it and leading to increased production of NADP+. The Ying et al. paper did not investigate whether the knockdown of Nadk led to a decrease in NADP+ or increased levels of NAD+ (by preventing the conversion of NAD+ to NADP+), which will be an important avenue of future research as increased NAD+ has been shown to improve many metabolic functions. These findings are also of interest for its potential clinical implications in that Nadk, being a kinase, is an enzyme that should be easily targetable by small-molecule drugs. A.S.G. is supported by ARS Project 8050-51000-097-02S, P30DK046200 , DK108722 , R21HD098056 , and the Robert C. and Veronica Atkins Foundation . The authors declare no competing interests. MiR-690, an exosomal-derived miRNA from M2-polarized macrophages, improves insulin sensitivity in obese miceYing et al.Cell MetabolismJanuary 14, 2021In BriefMiscommunication between adipose tissue macrophages (ATMs) and insulin target tissues is key to the development of insulin resistance, while it is known that lean ATM-derived exosomes promote insulin sensitivity. Here, Ying et. al show that miR-690 within ATM-derived exosomes directly increases insulin sensitivity both in vitro and in vivo. Full-Text PDF