Macrophage infiltration into obese adipose tissues suppresses the induction of UCP1 level in mice

Abstract

Emergence of thermogenic adipocytes such as brown and beige adipocytes is critical for whole body energy metabolism. Promoting the emergence of these adipocytes, which increase energy expenditure, could be a viable strategy in treating obesity and its related diseases. However, little is known regarding the mechanisms that regulate the emergence of these adipocytes in obese adipose tissue. Here, we demonstrated that classically activated macrophages (M1 Mϕ) suppress the induction of thermogenic adipocytes in obese adipose tissues of mice. Cold exposure significantly induced the expression levels of uncoupling protein-1 (UCP1), which is a mitochondrial protein unique in thermogenic adipocytes, in C57BL/6 mice fed a normal diet. However, UCP1 induction was significantly suppressed in adipose tissues of C57BL/6 mice fed a high-fat diet, into which M1 Mϕ infiltrated. Depletion of M1 Mϕ using clodronate liposomes eliminated the suppressive effect and markedly reduced the mRNA level of tumor necrosis factor-α (TNFα) in the adipose tissues. Importantly, consistent with the observed changes in the expression levels of marker genes for thermogenic adipocytes, combination treatment of clodronate liposome and cold exposure resulted in metabolic benefits such as lowered body weight and blood glucose level in obese mice. Moreover, intraperitoneal injection of recombinant TNFα protein suppressed UCP1 induction in lean adipose tissues of mice. Collectively, our data indicate that infiltrated M1 Mϕ suppress the induction of thermogenic adipocytes in obese adipose tissues via TNFα. This report suggests that inflammation induced by infiltrated Mϕ could cause not only insulin resistance but also reduction of energy expenditure in adipose tissues.

The dipeptidyl peptidase‐4 (DPP‐4) inhibitor teneligliptin enhances brown adipose tissue function, thereby preventing obesity in mice

“…Recent studies have shown that β‐adrenoreceptor‐induced activation of BAT function is suppressed under chronic inflammatory conditions induced by an increase in infiltrated macrophages in obese adipose tissue . Consistent with this previous report, Dpp4 expression levels in WAT have also been shown to be elevated in obese mice .…”

Inflammation of brown/beige adipose tissues in obesity and metabolic disease

“…However, similar to WAT, BAT from mice fed a sufficiently sustained obesogenic diet ultimately exhibit high mRNA levels of inflammation markers, including TNFα and F4/80. . The increased levels of pro‐inflammatory cytokines in BAT depots largely reflect enhancements in the presence and activity of infiltrated pro‐inflammatory immune cells; however, such cytokines may also be secreted by brown adipocytes, which can synthetize and release TNFα and MCP‐1, amongst other cytokines .…”

“…Diet‐induced obesity is also associated with decreased UCP1 expression; in some cases, however, some degree of obesity‐related inflammation is seen even in the presence of increased levels of UCP1 expression and BAT thermogenesis . However, even in these experimental settings, cold‐induced thermogenesis is severely impaired in BAT from diet‐induced obese mice and in obese humans . Experimental depletion of pro‐inflammatory macrophages was shown to eliminate the suppressive effect of diet‐induced obesity on the cold‐induced up‐regulation of UCP1 .…”

Brown and Beige Adipose Tissues in Health and Disease

“…Similarly, M1 and M2 macrophages appear to have opposing actions in BAT and/or beige fat. Clodronate liposome-induced depletion of M1 macrophages increases UCP1 expression in BAT and beige fat in mice with HFD-induced obesity (266). M1 macrophages secrete a variety of proinflammatory cytokines and chemokines, including TNFα and IL1β.…”

“…IL1β directly inhibits brown adipocyte differentiation in vitro (214). TNFα suppresses expression of β3 receptors in mouse adipocytes, thus attenuating β adrenergic signaling (21), and TNFα treatment attenuates cold-induced UCP1 expression in both BAT and iWAT in C57BL mice (265). A chronic treatment with a low dose of lipopolysaccharides (LPS), which stimulate M1 polarization, impairs beige adipogenesis and induces hypothermia in C57BL mice (230).…”