Adaptive Induction of Nonshivering Thermogenesis in Muscle Rather Than Brown Fat Could Counteract Obesity

Abstract

Warm-blooded animals such as birds and mammals are able to protect stable body temperature due to various thermogenic mechanisms. These processes can be facultative (occurring only under specific conditions, such as acute cold) and adaptive (adjusting their capacity according to long-term needs). They can represent a substantial part of overall energy expenditure and, therefore, affect energy balance. Classical mechanisms of facultative thermogenesis include shivering of skeletal muscles and (in mammals) non-shivering thermogenesis (NST) in brown adipose tissue (BAT), which depends on uncoupling protein 1 (UCP1). Existence of several alternative thermogenic mechanisms has been suggested. However, their relative contribution to overall heat production and the extent to which they are adaptive and facultative still needs to be better defined. Here we focus on comparison of NST in BAT with thermogenesis in skeletal muscles, including shivering and NST. We present indications that muscle NST may be adaptive but not facultative, unlike UCP1-dependent NST. Due to its slow regulation and low energy efficiency, reflecting in part the anatomical location, induction of muscle NST may counteract development of obesity more effectively than UCP1-dependent thermogenesis in BAT.

Fig. 1

Two-level regulation of thermogenesis in brown adipose tissue (BAT) and skeletal muscle. UCP1-dependent thermogenesis in BAT is activated by fatty acids released by lipolysis of intracellular triacylglycerols (TAG) in response to norepinephrine from sympathetic nerve endings. The same mechanism causes adaptive rise in Ucp1 expression and UCP1 content. Shivering is acutely stimulated by acetylcholine from motor nerve endings, activation of acetylcholine receptors and consecutive calcium release from sarcoplasmic reticulum through ryanodine receptors (RyR). Efficiency of calcium recycling is affected by interaction between sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase (SERCA) and sarcolipin (SLN). The activity of SLN is probably regulated mostly at the level of gene expression. SLN may represent a mechanism of adaptive, long-term tuning of regulatory pathway of shivering and/or shivering-independent mechanism of NST. Created with Biorender.com.

Fig. 2

Metabolic responses to acute and chronic cold exposure in mice (adapted from [7]). General increase of energy expenditure upon cold exposure reflects several thermogenic mechanisms. Muscle shivering and thermoregulatory tonus cover majority of heat production in response to acute cold stimulus. Continuing shivering leads to adaptation resembling exercise training, but shivering is gradually replaced by NST. NST mediated by UCP1 has a low capacity at thermoneutrality. However, if cold persist, capacity of UCP1-dependent NST adaptively rises and it gradually replaces shivering. It is facultative, i.e. it can be rapidly switched on and off due to its control by adrenergic nervous system (adrenergic thermogenesis). NST alternative to UCP1-mediated heat production, reflects several mechanisms, including NST in skeletal muscle. Preferential activation and adaptive increase of NST capacity in BAT or skeletal muscle depends on the genetic background of the mice. Control of muscle NST is probably relatively slow – it may not be facultative. Thus, when the contribution of muscle NST to total energy expenditure is relatively high compared to BAT (such as in A/J mice, see the main text), a substantial amount of energy is lost during the stay of cold-adapted mice in thermoneutral conditions. This phenomenon may contribute to resistance to obesity. Prolonged maintenance of cold-adapted animals at thermoneutral conditions results in reduction of the capacity of NST (not shown). Created with Biorender.com.