The evolving view of thermogenic fat and its implications in cancer and metabolic diseases

Abstract

The incidence of metabolism-related diseases like obesity and type 2 diabetes mellitus has reached pandemic levels worldwide and increased gradually. Most of them are listed on the table of high-risk factors for malignancy, and metabolic disorders systematically or locally contribute to cancer progression and poor prognosis of patients. Importantly, adipose tissue is fundamental to the occurrence and development of these metabolic disorders. White adipose tissue stores excessive energy, while thermogenic fat including brown and beige adipose tissue dissipates energy to generate heat. In addition to thermogenesis, beige and brown adipocytes also function as dynamic secretory cells and a metabolic sink of nutrients, like glucose, fatty acids, and amino acids. Accordingly, strategies that activate and expand thermogenic adipose tissue offer therapeutic promise to combat overweight, diabetes, and other metabolic disorders through increasing energy expenditure and enhancing glucose tolerance. With a better understanding of its origins and biological functions and the advances in imaging techniques detecting thermogenesis, the roles of thermogenic adipose tissue in tumors have been revealed gradually. On the one hand, enhanced browning of subcutaneous fatty tissue results in weight loss and cancer-associated cachexia. On the other hand, locally activated thermogenic adipocytes in the tumor microenvironment accelerate cancer progression by offering fuel sources and is likely to develop resistance to chemotherapy. Here, we enumerate current knowledge about the significant advances made in the origin and physiological functions of thermogenic fat. In addition, we discuss the multiple roles of thermogenic adipocytes in different tumors. Ultimately, we summarize imaging technologies for identifying thermogenic adipose tissue and pharmacologic agents via modulating thermogenesis in preclinical experiments and clinical trials.

Dynamic changes of immunocyte subpopulations in thermogenic activation of adipose tissues

“…The other was the mMCP-counter algorithm, which analyzed the abundance of 16 types of murine immune and stromal cells. Consistent with the thermogenic activation of brown fat in acute cold ( 25 , 26 ), most datasets showed changes started as early as a cold duration of 6h in BAT. These algorithm analyses revealed that beige adipogenesis might occur during longer periods of cold exposure, as 35d long-term cold acclimation resulted in more significant changes in immune cells in SAT ( Table 1 ).…”

“…Some significant changes in immune cells, including naïve T (both CD4 + and CD8 + ) cells and memory T (both CD4 + and CD8 + ) cells were only discovered in BAT, but not in SAT. These differences might reveal inherent unique characteristics of BAT during cold exposure, as brown adipocytes are activated rapidly in response to acute cold challenge, while beige adipocytes in SAT are transdifferentiated from white adipocytes or derived from white pre-adipocytes ( 26 ). Immune cells and adipocytes in adipose tissues may interact during these processes, resulting in different changes in immune cells in BAT from those in SAT.…”

The Chinese herbal medicine Dai-Zong-Fang promotes browning of white adipocytes in vivo and in vitro by activating PKA pathway to ameliorate obesity

“…Beige adipocytes improve energy metabolism by enhancing non-shivering thermogenesis. Promoting the browning of WAT is a research hotspot of obesity intervention ( Yin et al, 2022 ).…”

Adipose Tissue Targeting Ultra‐Small Hybrid Nanoparticles for Synergistic Photodynamic Therapy and Browning Induction in Obesity Treatment

“…[16,17] WAT exists in excess energy in the form of triacylglycerol (TAG), while thermogenic adipose tissue dissipates energy as heat. [18][19][20][21][22][23] Although both aforementioned strategies are promising, they also possess respective superiority and drawbacks. PDT works rapidly and directly but is only suitable for superficial treatment as limited by light penetration depth.…”