Cold and Exercise: Therapeutic Tools to Activate Brown Adipose Tissue and Combat Obesity

Abstract

The rise in obesity over the last several decades has reached pandemic proportions. Brown adipose tissue (BAT) is a thermogenic organ that is involved in energy expenditure and represents an attractive target to combat both obesity and type 2 diabetes. Cold exposure and exercise training are two stimuli that have been investigated with respect to BAT activation, metabolism, and the contribution of BAT to metabolic health. These two stimuli are of great interest because they have both disparate and converging effects on BAT activation and metabolism. Cold exposure is an effective mechanism to stimulate BAT activity and increase glucose and lipid uptake through mitochondrial uncoupling, resulting in metabolic benefits including elevated energy expenditure and increased insulin sensitivity. Exercise is a therapeutic tool that has marked benefits on systemic metabolism and affects several tissues, including BAT. Compared to cold exposure, studies focused on BAT metabolism and exercise display conflicting results; the majority of studies in rodents and humans demonstrate a reduction in BAT activity and reduced glucose and lipid uptake and storage. In addition to investigations of energy uptake and utilization, recent studies have focused on the effects of cold exposure and exercise on the structural lipids in BAT and secreted factors released from BAT, termed batokines. Cold exposure and exercise induce opposite responses in terms of structural lipids, but an important overlap exists between the effects of cold and exercise on batokines. In this review, we will discuss the similarities and differences of cold exposure and exercise in relation to their effects on BAT activity and metabolism and its relevance for the prevention of obesity and the development of type 2 diabetes.

Keywords: 12,13-diHOME; FGF21; VEGF; brown adipose tissue; cold; exercise; glucose; lipids; obesity; phospholipids.

Figure 1

Effects of cold exposure and exercise on BAT. (A) Exercise and (B) cold exposure effects on BAT metabolism can cause the release of batokines, which act in an autocrine, paracrine, or endocrine manner to influence metabolic health. (A) Exercise reduces insulin-stimulated glucose uptake in BAT, suppresses triglyceride (TAG) accumulation, and lowers mitochondrial lipids, such as cardiolipin (CL) and lysophosphatidylglycerol (LPG), which could affect the thermogenic capacity of BAT. Conversely, exercise training stimulates epoxide hydrolase 1 and 2 (Ephx1/2), and increases the synthesis of the lipokine 12,13-diHOME. The effects of exercise on mitochondrial activity, fibroblast growth factor 21 (FGF21) and vascular endothelial growth factor A (VEGFA) production are unknown. (B) Exposure to cold temperatures stimulates insulin-stimulated glucose uptake in BAT, synthesis of CL and LPG, and secretion of batokines FGF21 and VEGFA that lead to increased insulin sensitivity and tissue vascularization. Additionally, cold exposure increases the synthesis of 12,13-diHOME, which can act in an autocrine manner to promote fatty acid uptake in BAT, ultimately leading to increased TAG and UCP1-mediated thermogenesis.