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We recently exploited a transgenic approach to coerce macrophage anti-inflammatory M2 polarizationin vivoby lowering Receptor Interacting Protein 140 (RIP140) level in macrophages (mϕRIP140KD), which induced browning of white adipose tissue (WAT).In vitro, conditioned medium from cultured adipose tissue macrophages (ATMs) of mϕRIP140KD mice could trigger preadipocytes' differentiation into beige cells. Here we describe a cell therapy for treating high fat diet (HFD)-induced insulin resistance (IR). Injecting M2 ATMs retrieved from the WAT of mϕRIP140KD mice into HFD-fed obese adult wild-type mice effectively triggers their WAT browning, reduces their pro-inflammatory responses, and improves their insulin sensitivity. These data provide a proof-of-concept that delivering engineered anti-inflammatory macrophages can trigger white fat browning, stimulate whole-body thermogenesis, and reduce obesity-associated IR. [ABSTRACT FROM PUBLISHER]

Excessive nutrient intake in obesity triggers the accumulation of various types of immune cells in adipose tissue, particularly visceral adipose tissue (VAT). This can result in chronic inflammation which disrupts insulin effects on adipocytes and muscle cells and culminates in development of insulin resistance. The interplay between immune cells and adipose tissue is a key event for the development of insulin resistance that precedes type 2 diabetes. CD40, a well-documented costimulatory receptor, is required for efficient systemic adaptive immune responses. However, we and other groups recently showed that CD40 unexpectedly ameliorates inflammation in VAT and accordingly attenuates obesity-induced insulin resistance. Specifically, although CD40 is typically considered to play its principal immune roles on B lymphocytes and myeloid cells, we found that CD40+CD8+T lymphocytes were major contributors to the protective effect. This unexpected inhibitory role of CD40 on CD8+T cell activation in VAT may reflect unique features of this microenvironment. Additional knowledge gaps include whether CD40 also plays roles in mucosal immunity that control the homeostasis of gut microbiota, and human metabolic diseases. Potential therapeutic approaches, including stimulating CD40 signaling and/or manipulating specific CD40 signaling pathways in the VAT microenvironment, may open new avenues for treatment of obesity-induced insulin resistance, and prevention of type 2 diabetes. [ABSTRACT FROM AUTHOR]

A “Holy Grail” sought in medical treatment of obesity is to be able to biologically reprogram their adipose tissues to burn fat rather than store it. White adipose tissue (WAT) stores fuel and its expansion underlines insulin resistance (IR) whereas brown adipose tissue (BAT) burns fuel and stimulates insulin sensitivity. These two types of fats seesaw within our bodies via a regulatory mechanism that involves intricate communication between adipocytes and blood cells, particularly macrophages that migrate into adipose deposits. The coregulator, Receptor Interacting Protein 140 (RIP140), plays a key role in regulating this communication. In mice on a high-fat diet, the level of RIP140 in macrophages is dramatically elevated to activate their inflammatory M1 polarization and enhance their recruitment into WAT, facilitating IR. Conversely, lowering the level of RIP140 in macrophages not only reduces M1 macrophages but also expands alternatively polarized, anti-inflammatory M2 macrophages, triggering white adipose tissue browning, fat burning, and restoration of insulin sensitivity. This suggests a potential therapeutic strategy for reversing IR, obesity, and atherosclerotic or even cosmetic fat deposits: therapeutic browning of white adipose deposits by diminishing RIP140 levels in macrophages. [ABSTRACT FROM PUBLISHER]