PMC

Analysis of PET images using the torso-mantle method demonstrating ¹⁸F-FDG uptake in BAT depots located in the cervical-supraclavicular-thoracic region during exposure to 19°C in a 26-year-old man (A). No FDG uptake was visible when the scan was performed at 24°C (B). Correlations between BAT uptake, age, and cold-induced thermogenesis are shown. C, Correlation between cold-induced thermogenesis (expressed as the difference in EE between 19°C and 24°C) and BAT activation (SUV). D, Correlation between cold-induced thermogenesis and age. Square symbols, females; round symbols, males; filled symbols, BAT positive; empty symbols, BAT negative. Bottom, Stepwise regression analysis for independent contribution to cold-induced thermogenesis.

A Total EE. B Cold-induced thermogenesis (CIT). Black columns, High-BAT group; white columns, Low-BAT group. Values are mean ± SD. *P < 0.05 between the groups.

Based on the current knowledge of bioenergetics, four potential therapeutic approaches could be envisioned: (1) increasing brown fat differentiation from progenitor cells, (2) activating brown fat thermogenesis, (3) promoting skeletal muscle thermogenesis: or (4) increasing general mitochondrial uncoupling. For skeletal muscle, there are three types of thermogenesis: exercise-induced thermogenesis, non-exercise activity thermogenesis, and cold-induced shivering thermogenesis. Thus, therapeutic interventions that mimic these mechanisms could potentially increase muscle’s thermogenic capacity and counteract obesity. This is especially beneficial to individuals with physical limitations in exercising or those who are genetically predisposed to obesity. All of these approaches can be applied in the conventional pharmaceutical approaches of developing drugs and/or using natural food components targeting key pathways of cellular bioenergetics. Alternatively, there is a cell-based therapy where progenitors are isolated from patients during liposuction or biopsy, manipulated ex vivo by treating them with factors that promote BAT differentiation or transfecting them with genes specifying BAT differentiation, then transplanted these cells back into the same individual to generate a functional brown fat to help dissipate excess energy.

A Body temperature in male chow-fed 2-month-old D1KO and fl/fl mice during acute 5 °C cold exposure (n = 6 for fl/fl and 5 for D1KO). *Indicates statistical significance between fl/fl and D1KO as analyzed by two-tailed unpaired Student’s t-test. B Body temperature change in male chow-fed 2-month-old D1KO and fl/fl mice after 3 h of cold exposure (n = 6 for fl/fl and 5 for D1KO). *Indicates statistical significance between fl/fl and D1KO as analyzed by two-tailed unpaired Student’s t-test. C, D Quantitative RT-PCR analysis of BAT-specific gene expression (C, n = 6 for fl/fl and 8 for D1KO), and myogenic gene expression (D, n = 7 for fl/fl and 6 for D1KO) in iBAT of male chow-fed 2-month-old D1KO and fl/fl mice after an acute 4-h 5 °C cold exposure. *Indicates statistical significance between fl/fl and D1KO as analyzed by two-tailed unpaired Student’s t-test in (C) and Mann–Whitney’s nonparametric U test in (D). E, F Quantitative RT-PCR analysis of BAT-specific gene expression (E, n = 6/group), and myogenic gene expression (F, n = 6/group) in iBAT of male chow-fed 2-month-old D1KO and fl/fl mice after a chronic 7-day 5 °C cold exposure. *Indicates statistical significance between fl/fl and D1KO as analyzed by two-tailed unpaired Student’s t-test in (E) and Mann–Whitney’s nonparametric U test in (F). G Immunoblotting of UCP1 protein in iBAT of male chow-fed 2-month-old D1KO and fl/fl mice after a 7-day 5 °C cold exposure (n = 4/group). *Indicates statistical significance between fl/fl and D1KO as analyzed by two-tailed unpaired Student’s t-test. H, I Representative H&E staine (H) and UCP1 IHC staining (I) in iBAT from male chow-fed 2-month-old D1KO and fl/fl mice after a chronic 5 °C 7-day cold exposure (n = 3 replicates for each group). All data are expressed as mean ± SEM.