MECHANISMS IN ENDOCRINOLOGY: Human brown adipose tissue as a therapeutic target: warming up or cooling down?

Abstract

Excessive accumulation of white adipose tissue leads to obesity and its associated metabolic health consequences such as type 2 diabetes and cardiovascular disease. Several approaches to treat or prevent obesity including public health interventions, surgical weight loss, and pharmacological approaches to reduce caloric intake have failed to substantially modify the increasing prevalence of obesity. The (re-)discovery of active brown adipose tissue (BAT) in adult humans approximately 15 years ago led to a resurgence in research into whether BAT activation could be a novel therapy for the treatment of obesity. Upon cold stimulus, BAT is activated and generates heat to maintain body temperature, thus increasing energy expenditure. Activation of BAT may provide a unique opportunity to increase energy expenditure without the need for exercise. However, much of the underlying mechanisms surrounding BAT activation are still being elucidated and the effectiveness of BAT as a therapeutic target has not been realised. Research is ongoing to determine how best to expand BAT mass and activate existing BAT; approaches include cold exposure, pharmacological stimulation using sympathomimetics, browning agents that induce formation of thermogenic beige adipocytes in white adipose depots, and the identification of factors secreted by BAT with therapeutic potential. In this review, we discuss the caloric capacity and other metabolic benefits from BAT activation in humans and the role of metabolic tissues such as skeletal muscle in increasing energy expenditure. We discuss the potential of current approaches and the challenges of BAT activation as a novel strategy to treat obesity and metabolic disorders.

Increased expression level of ANGPTL8 in white adipose tissue under acute and chronic cold treatment

“…Among the many roles that WAT plays in physiology, its role as an energy store during cold treatment is critical for directing lipids toward BAT for thermogenesis. The response of adipose tissue to cold demonstrates the highly dynamic and elastic nature of this tissue [ 9 , 14 , 19 ]. For instance, when exposed to extended cold treatment, WAT differentiates into beige/brite adipocytes.…”

“…WAT primarily functions as a lipid storage tissue and is the primary source of energy, particularly during fasting [ 13 ]. In contrast, BAT plays a major role in regulating energy expenditure during cold exposure by enhancing mitochondrial heat production via a nonshivering mechanism [ 9 , 14 ]. Bartelt et al reported that short-term cold exposure results in increased BAT activity, which enhances TG uptake in a process that relies on LPL enzyme activity [ 15 ].As the ANGPTL protein family members are important regulators of TG metabolism in the adipose tissue, several studies have focused on the role of ANGPTL4 in cold treatment [ 16 , 17 ].…”

Increased expression level of ANGPTL8 in White Adipose tissue under Chronic Cold Treatment

“…Adipose tissue response to cold demonstrates the elasticity and the highly dynamic state this tissue possesses [11,14,19]. This is clearly shown in the WAT tissue response to extended cold treatment where it can be differentiated into what is called beige or brite adipocytes [11,14,19]. Like BAT, beige cells exhibit a high level of UCP1 and many mitochondria with high thermogenetic capacity.…”

“…On the other hand, brown adipocytes are a powerhouse that consumes a large amount of energy which can enhance energy expenditure and alleviates insulin resistance by creating a negative energy balance [11][12][13]. Brown adipose tissue facilitates the mitochondrial heat production through a non-shivering mechanism that uncouples ATP production from substrate metabolism [11,14]. Moreover, shifting white adipocytes into brown or beige adipocytes is a eld of high value as it constitutes a mechanism to increase energy expenditure and enhance metabolic function.…”

“…Moreover, shifting white adipocytes into brown or beige adipocytes is a eld of high value as it constitutes a mechanism to increase energy expenditure and enhance metabolic function. Adipocyte browning is a natural process that is induced by cold treatment or by exercise [11,14]. LPL is one enzyme that has been shown to be activated by short cold exposure [15].…”