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 activates 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.

Figure 1

The energy balance equation and current pharmacotherapy to achieve weight loss. Energy balance is governed by the relationship between energy input (calories consumed) and energy output (energy expended). Obesity results from a chronic imbalance of energy intake exceeding energy expenditure with storage of this excess energy as triglycerides mainly in white adipose tissue. All licensed anti-obesity medications primarily cause weight loss by reducing appetite/energy intake (*indicates licensed to treat obesity in US only, ^†indicates currently withdrawn). Basal metabolic rate, physical activity, diet-induced thermogenesis (DIT) and cold-induced thermogenesis (CIT) all contribute to total energy expenditure. Brown adipose tissue (BAT) is located in adult humans primarily in the cervical, supraclavicular, axillary, paravertebral and peri-renal regions. BAT activation is a key component of both CIT and DIT and is an attractive target to increase energy expenditure to treat obesity. 5HT, 5-hydroxytryptamine; GLP-1, glucagon-like peptide 1; POMC, pro-opiomelanocortin.

Figure 2

Brown adipocyte activation and molecular mechanism of UCP1 function. Upon cold stimulus, sympathetic neurons innervating BAT release noradrenaline (NADR) from the synapse. NADR binds to various β-adrenergic receptors (β-AR) on the brown adipocyte which activates adenylyl cyclase (AC), converting ATP to cyclic adenosine monophosphate (cAMP). cAMP activates protein kinase A (PKA) which stimulates the lipolysis of triglyceride stores and release of fatty acids (FA). FAs are the primary substrate for thermogenesis but also bind and activate uncoupling protein 1 (UCP1) located in the mitochondria. UCP1 generates heat via transport of protons (H⁺) across the inner mitochondrial member using the electrochemical proton gradient generated by the electron transport train, uncoupling respiration from ATP synthase. Uptake of circulating free fatty acids (FFA) and glucose contribute to the regeneration of intracellular triglyceride stores, additionally glucose can be oxidised and enter the tricarboxylic acid (TCA) cycle. FFAs are transported into the cell by fatty acid transport protein (FATP, fatty acid binding protein (FABP), and cluster of differentiation 36 (CD36). Glucose is transported into the cell via the glucose transporters GLUT1 and 4. C1–4, complex 1–4; CoQ, co-enzyme Q; Cyto C, cytochrome C; e⁻, electron.

Figure 3

Whole body cold-induced thermogenesis and substrate utilisation. (A) Cold exposure stimulates WAT lipolysis to provide FAs for utilisation by both BAT and skeletal muscle (grey arrows). BAT uses FAs released from intracellular triglyceride stores to fuel non-shivering thermogenesis (orange arrow) but also sequesters circulating FAs and glucose. Skeletal muscle shivering accounts for the largest proportion of whole body heat production, glucose and FA uptake during cold-induced thermogenesis (CIT) (pink arrows). Muscles that contribute substantially to shivering thermogenesis include the longus colli, sternocleidomastoid, pectoralis major, and the rectus femoris. (B) During cold exposure, glucose uptake per gram of tissue is greater in BAT than skeletal muscle but with similar fatty acid uptake. However, whole body FA and glucose uptake by BAT is comparatively low due to substantially greater skeletal muscle mass. (C) Quantification of CIT varies greatly depending on the cooling method used and temperature, ambient air cooling protocols (orange columns) typically elicit a lower increase in energy expenditure compared to water cooling blanket/suit protocols (blue columns), but substantial CIT is induced by both methods. Additional references used for data in panel C (168,169).

Figure 4

Factors that induce browning of typical WAT depots. An illustration of factors that induce thermogenic beige adipocyte formation in vivo and in vitro with greater UCP1 expression and uncoupled respiration compared to white adipocytes. The small number of factors that induce browning of white adipose tissue in vivo in humans are highlighted in red and underlined. *BMP8b is classed additionally as a BATokine. 12,13-diHOME, 12,13-dihydroxy-9Z-octadecenoic acid; β-AR, β-adrenoreceptor; BMP, bone morphogenic protein; BNP, brain natriuretic peptide; FGF21, fibroblast growth factor-21; IL, interleukin; NRG4, neuregulin-4; PPARγ, peroxisome proliferator-activated receptor-γ.