Cold‐Induced Lipokines in Metabolism

Metabolic syndrome and obesity are rapidly increasing worldwide, leading to high morbidity and mortality in type 2 diabetes, cardiovascular disease, renal failure, and cancers. Fundamental to these pathologies is adipose tissue. Besides the energy‐storing white adipose tissue, brown and brown‐like beige adipose tissue (BAT) are specialized for thermogenic energy expenditure. Because of the high capacity of BAT in consuming nutrients to generate heat and dissipate energy and the presence of BAT in adult humans, enhancing the quantity or activity of BAT has been regarded as an appealing approach for the treatment or prevention of obesity and its related metabolic disorders. Besides energy dissipation, at least part of BAT's beneficial effects is mediated via its secretory function and the resulting capacity to affect metabolic functions in other tissues such as muscle, WAT, and liver. BAT can produce factors, such as peptides, lipids, or other metabolites, which may act in an endocrine, paracrine, or autocrine manner to regulate physiological functions required for adaptive thermogenesis. Cold exposure is one of the most efficient ways to activate BAT and increases energy consumption. Short‐term cold exposure leads to significant improvement in insulin sensitivity. By utilizing mass spectrometry‐based lipidomics, we have identified novel lipid mediators (i.e., lipokines) derived from BAT, whose concentrations are increased in the circulation of cold exposed mice and humans. These lipokines act as markers and stimulators of thermogenic activity and negatively associate with body mass index and insulin sensitivity. At the molecular level, cold exposure activates the expression of key enzymes that regulate the biosynthesis of the lipokines. Mechanistic studies illustrate that cold‐induced lipokines can modulate glucose and fatty acid metabolism. These findings provide novel therapeutic strategies for the treatment of metabolic diseases by producing lipokines mimicking cold exposure.