Thermogenic adipose tissue as a therapeutic target: from human heterogeneity to pharmacological translation

Abstract

Thermogenic adipose tissue, including classical brown adipose tissue (BAT) and inducible beige adipocytes, has re-emerged as a promising therapeutic target in the obesity field. Because BAT can convert chemical energy into heat while also playing a role in regulating systemic glucose and lipids. However, transforming a laboratory breakthrough into a practical treatment has proven to be more of a marathon than a sprint. Two main obstacles keep hindering progress. First, we still primarily “see” human BAT through imaging surrogates rather than directly measuring its actual thermogenic output. More importantly, we have learned the hard way that mechanistic insights from inbred rodents often do not translate well to the complex, varied fat depots in humans. In this review, we argue that it is time to move beyond relying solely on 18 F-fluorodeoxyglucose ([^18F]FDG) uptake. We propose a multimodal framework that carefully distinguishes three different states: whether the tissue is present, whether it has been acutely recruited, and whether it is actively functioning. We also explore recent atlas-scale data, which shows that these thermogenic depots are far from uniform. They heavily depend on their specific microenvironment and vary widely from person to person. This inherent “patchiness” helps explain why some individuals respond to certain triggers while others do not. Additionally, the mechanistic landscape has expanded well beyond the traditional uncoupling protein 1 (UCP1)-driven model. We now need to consider UCP1-independent energy pathways, mitochondrial quality-control loops, and the complex “crosstalk” between different organs. Ultimately, turning BAT into a viable clinical tool requires a much stronger alignment between basic mechanisms and the clinical setting. We won’t see real progress until our study designs focus more on endpoints and are far more sensitive to human diversity. The goal isn’t just to see if we can activate the tissue, but to determine what truly constitutes a meaningful functional benefit for a patient.