Obesity develops when there is an imbalance between energy intake and expenditure. A brown adipose tissue (BAT) is a specialized adipose tissue involved in thermogenesis and energy dissipation in response to cold.
This new study (1) published in Cell indicates, that strangely, BAT response to cold is mediated via cytokine IL-4.
The authors in this study wanted to understand how type 2 immunity (Th2 response dominated by IL-4 and IL-13) affects cold-induced brown fat remodeling.
To this end, wild-type or IL-4 /IL-13 double KO mice were exposed to thermoneutral (30C), sub-neutral (22C) and cold temperature (5C) and subcutaneous white adipose tissue response were examined. Unlike wild-type mice, IL-4 /IL-13 double KO mice did not show response to cold.
Similarly, IL-4ra KO mice did not show response to cold.
Examination of subcutaneous white adipose tissue (scWAT) in STAT6 KO mice confirmed that IL-4 signaling was crucial for thermogenic response to cold.
To understand what cell type was producing IL-4, the authors examined 4get mouse that express GFP protein from endogenous IL-4 locus. Expression pattern indicated that IL-4 producers were eosinophils. Indeed, using 4get mice deficient in eosinophils, the authors could abrogate cold response in scWAT.
In addition, the authors found that mice deficient for CCR2 also lacked scWAT response to cold. CCR2 is required for recruitment of macrophages into tissue.
To authors speculated that IL-4 driven macrophage-specific tyrosine hydroxylase (TH) expression was responsible for scWAT response to cold. To test this hypothesis, they have generated mice with specific deletion of tyrosine hydroxylase in macrophages. Indeed, this TH f/f Lyz2-cre mice lacked scWAT browning response to cold.
Finally, to examine the role of exogenous IL-4 on browning of scWAT, the authors injected mice, fed with high-fat diet, with IL-4/anti-IL-4 complexes to mimic efficient IL-4 signaling. Such treatment mimicked cold-response in scWAT with corresponding body fat and mass reduction and increase in insulin sensitivity.
In summary, the authors showed that long-held idea that cold response is neuronal driven response is outdated. It appears that type 2 immune response, specifically, eosinophil-derived IL-4 stimulates local macrophage-specific tyrosine hydroxylase activity and catecholamine production leading to local browning of scWAT and thermogenic response.
Of course, it is very interesting to know how eosinophils are sensing cold or suboptimal temperature. I think it will be a local commensial microbiota-induced effect.
The idea that immune system can sense a temperature gradient is quite surprising in itself. Though almost everyone can affirm common observation that when children or even adults happened to fall asleep in the couch, others are trying to cover them with blanket to prevent them from getting or catching a “cold”. Does such empirical observation imply that cold-induced type 2 response has its undesirable effects?