Abstract
Thermogenic adipocytes present a promising therapeutic strategy for metabolic diseases. While murine models have provided valuable insights into thermogenic adipose tissue, their relevance to human physiology is constrained by species-specific differences in tissue distribution and thermogenic capacity. In vitro human models offer a more controlled platform to study adipocyte differentiation, addressing challenges such as limited access to deep fat depots and individual variability. This systematic review summarizes the current literature on human in vitro models for thermogenic adipocyte induction, encompassing 117 studies involving primary human adipocyte progenitors differentiated into thermogenic adipocytes in 2D cultures. Most studies relied on classical adipogenic inducers, including isomethylbutylxanthine, dexamethasone, and insulin, with additional use of triiodothyronine, rosiglitazone, or indomethacin. A few studies incorporated adrenergic stimulation or exposure to lower temperatures to simulate cold exposure. Notably, some studies demonstrated successful differentiation under serum-free, chemically defined conditions, highlighting their potential for reproducibility and translational relevance. A key limitation remains the predominant reliance on gene expression as the primary outcome, with few studies assessing mitochondrial respiration or broader metabolic functions. Moving forward, the development and adoption of standardized, functionally validated protocols will be critical to fully realize the potential of human in vitro thermogenic adipocyte models in metabolic research.