Nature sub-publication: Air conditioning not only keeps you cool, but also helps you lose weight! Kill two birds with one stone!

With the improvement of living standards, "obesity/overweight" has become a major problem that troubles most of us foodies. Obesity is associated with many non-communicable diseases, including cardiovascular disease, type 2 diabetes and cancer, and has become a major health problem worldwide.

"Sweat like rain and burn fat" has become the "golden standard" for weight loss that many obese people regard as a guiding principle.

However, is this "all-over-heat" weight loss method really healthy?

Recently, a research paper titled "Brown adipose tissue-derived MaR2 contributes to cold-induced resolution of inflammation" was published in Nature metabolism by Yuhua Zeng's team from Harvard Medical School. The researchers found that low temperature can reduce inflammation caused by obesity through the production of lipid molecules Maresin 2 (MaR2) in brown adipose tissue (BAT), increase insulin sensitivity and glucose tolerance in obese mice, and provide a new method and strategy for the treatment of obesity.

During the development of obesity, immune cells such as macrophages, neutrophils and lymphocytes gradually accumulate in insulin-sensitive tissues and interfere with insulin signals in the body, while releasing pro-inflammatory factors (such as tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β)) to produce chronic inflammation and cause metabolic disorders. This is the main way obesity damages our health.

In the process of chronic inflammation caused by obesity, our body will also produce a corresponding resistance process. This "inflammatory resolution" process is achieved through specialized pro-resolving mediators (SPM). SPM is an enzyme substance derived from essential fatty acids. It inhibits inflammatory responses and promotes inflammation resolution during the resolution of tissue inflammation. A large number of studies have shown that chronic inflammation caused by obesity is related to SPM synthesis disorders. The lipid molecule Maresin 2 (MaR2) is a type of SPM, and its role in the inflammatory process of obesity remains to be studied.

Studies have shown that low temperatures can improve insulin sensitivity in humans, but the mechanism has not yet been fully elucidated. Cold stimulation can stimulate brown adipose tissue to produce heat. However, its role in chronic inflammation caused by obesity remains to be studied.

Fig.1 Cold exposure reduces inflammation and insulin resistance and improves glucose tolerance in DIO mice.

To explore whether low temperature can improve chronic inflammation and metabolic disorders caused by obesity. The researchers first kept obese mice (DIO) and normal mice in cold (5°C) and hot (30°C) for 7 days. The results showed that low temperature significantly reduced the body weight of both groups of male mice, which may be due to the reduction in fat and liver weight. In addition, low temperature significantly improved the blood glucose and insulin levels of mice increased by a high-fat diet, and reduced the high TNF-α levels (the main pro-inflammatory factor) induced by a high-fat diet. These results were the same in female mice, indicating that there is no gender difference in the improvement of obesity inflammation by low temperature.

Fig.2 Cold resolves obesity-induced inflammation in BAT and liver of DIO mice.

Next, in order to determine whether weight loss affects insulin resistance, glucose tolerance and inflammation in the 7-day low temperature, the researchers conducted a short-term low temperature experiment. The results showed that low temperature improves obesity inflammation and insulin resistance before weight loss, which is not affected by weight changes.

Further, the researchers explored whether low temperature improves obesity inflammation and is related to specific tissues and organs. The results showed that a 14-week high-fat diet produced severe inflammation in the adipose tissue and liver of mice. Inflammation in white adipose tissue is the main site. Inflammation is associated with high expression of genes such as Adgre1 (F4/80), CCL2, Ccr2, Itgax (CD11c), TNF-α and II1β in macrophages. Although low temperature improves most systemic inflammation caused by obesity, it has no effect on epididymal and inguinal white adipose tissue. Moreover, the improvement effect of low temperature is not due to changes in the inflammatory response in white adipose tissue, but the existence of other mechanisms.

Fig.3 Cold increases DHA-derived MaR2 and related structural isomers in BAT and liver of DIO mice. a, Schematic of the MaR2 biosynthetic

In addition, the researchers found that low temperature can reduce the progression of liver fibrosis by reducing the expression of TLR2 and TGFβ1. This process was achieved by reducing the level of triglycerides and other fat synthesis genes in the liver of mice. By comparison, the researchers found that the process of low temperature reducing liver inflammatory response was before the changes in liver lipid accumulation.

Fig.4 BAT secretes MaR2 isomers in circulation

Through liquid chromatography-tandem mass spectrometry, the researchers found that low temperature increased DHA-derived MaR2 and its isomers in brown adipose tissue and liver. Further, the researchers quantified the production of the Maresin pathway in the liver, and the results showed that low temperature increased the products of the MaR2 pathway in brown adipose tissue and protected the liver, while more experimental results showed that these reactions occurred in brown adipose tissue rather than the liver.

Fig.5 BAT-specific loss of Alox12 increases inflammation in the CRE/Alox12-KD obese male mice using UCP1CRE and CRISPR-C

Finally, the researchers verified the above results in human volunteers and found that low temperature can stimulate activated brown adipose tissue to secrete products of the Maresin pathway into the circulation of mice and humans, and these results are consistent with the experimental results in mice.

In summary, this study shows us a treatment method that can achieve resistance to obesity through physical form alone. This strategy is simple and has no side effects, and has great application prospects compared to the currently commonly used immunosuppressants.

Of course, this research also provides strong theoretical support for the majority of "fat people" to use air conditioning in the summer!

References:

1.Endle, et al. AgRP neurons control feeding behavior at cortical synapses via peripherally derived lysophospholipids. Nat Metab 4, 683–692 (2022).