Taming the Flames: Targeting White Adipose Tissue Browning in Hypermetabolic Conditions

Abstract

In this era of increased obesity and diabetes prevalence, the browning of white adipose tissue (WAT) has emerged as a promising therapeutic target to induce weight loss and improve insulin sensitivity in this population. The browning process entails a shift in the WAT from primarily storing excess energy to the dissipation of energy as heat. However, this idealistic view of WAT browning being the savior of the metabolic syndrome has been criticized by studies in burn and cancer patients that have shown browning to be detrimental rather than beneficial. In fact, in the context of hypermetabolic states, the browning of WAT has presented with substantial clinical adverse outcomes related to cachexia, hepatic steatosis, and muscle catabolism. Therefore, the previous thought construct of understanding browning as an all-beneficial physiologic event has now been met with skepticism. In this review, we focus on current knowledge of browning of WAT and its adverse metabolic alterations during hypermetabolic states. We also discuss the regulators and signaling pathways involved in the browning process and their potential for being targeted by new or existing drugs to inhibit or alleviate browning, potentially leading to decreased hypermetabolism and improved clinical outcomes. Lastly, the imminent clinical applications of pharmacological agents are explored in the perspective of attenuating WAT browning and its associated adverse side effects reported in burn patients.

Figure 1.

Anatomical locations and properties of the different adipose tissue depots in humans and mice. Left panel, top: human BAT (acquired from the supraclavicular region of a burn patient) is characterized by a multiocular morphology and increased staining for the UCP1. Middle: browning of subcutaneous white adipose (induced by burn injury in the image illustrated) leads to the formation of multiocular and UCP1-expressing beige/brite adipocytes. Bottom: human WAT (acquired from subcutaneous abdominal depot) have uniocular morphology and do not stain positive for the UCP1. Right panel, top: mice BAT (acquired from interescapular region) showing multiocular morphology and increased staining for the UCP1 protein. Middle: browning of inguinal WAT (induced by mice subjected to a 30% total body surface area burn injury) results in the formation of a multiocular and UCP1-expressing beige/brite adipocytes. Bottom: mice WAT (acquired from inguinal depot) have uniocular morphology and do not stain positive for the UCP-1 protein.

Figure 2.

Context-dependent metabolic effects of browning. Left panel: activation of browning results in beneficial metabolic effects (green) in obesity, mediated by both fat catabolism and paracrine factors, released postbrowning like fibroblast growth factor 21 (FGF-21). Right panel: conversely, activation of browning in hypermetabolic conditions (burns, cancer) leads to adverse side effects (red), namely cachexia, hepatic steatosis, lean muscle loss, and, ultimately, impairments in wound healing.