Regulation of Energy Expenditure and Brown/Beige Thermogenic Activity by Interleukins: New Roles for Old Actors

Abstract

Obesity rates and the burden of metabolic associated diseases are escalating worldwide Energy burning brown and inducible beige adipocytes in human adipose tissues (ATs) have attracted considerable attention due to their therapeutic potential to counteract the deleterious metabolic effects of nutritional overload and overweight. Recent research has highlighted the relevance of resident and recruited ATs immune cell populations and their signalling mediators, cytokines, as modulators of the thermogenic activity of brown and beige ATs. In this review, we first provide an overview of the developmental, cellular and functional heterogeneity of the AT organ, as well as reported molecular switches of its heat-producing machinery. We also discuss the key contribution of various interleukins signalling pathways to energy and metabolic homeostasis and their roles in the biogenesis and function of brown and beige adipocytes. Besides local actions, attention is also drawn to their influence in the central nervous system (CNS) networks governing energy expenditure.

Keywords: brown and beige adipose tissue; cytokines; energy and metabolic homeostasis; inflammation; interleukins; thermogenesis.

Figure 1

Main interleukins involved in the modulation of EE and BAT and beige adipose tissue thermogenesis through CNS or direct actions in brown adipocytes activation and WAT browning. In case of available data, tissue and cell sources of this immune mediators are also shown. Red or green lines and arrows depict inhibitory or stimulatory actions. Inset in the upper panel represents a scheme of the main hypothalamic and brain stem nucleus involved in the central regulation of ATs thermogenic function, namely: preoptic area (POA), dorsomedial (DMH), arcuate (ARC), paraventricular (PVH) and lateral nucleus of the hypothalamus (LH) as well as the rostral raphe nucleus (rRPA) at the brain stem. Hypothalamic mediators at these nuclei include: agouti-related protein (AgRP), neuropeptide Y (NPY) and proopiomelanocortin (POMC) at the ARC, orexin at the LH and transient vanilloid rector 4 (TRPV4) at the POA. IL6 and IL15 are known to activate or inhibit these central pathways. rRPA receives input from the different hypothalamic areas to activate sympathetic projections to ATs acting at β3 adrenoceptors (B3-AR). Some interleukins are directly produced by resident or recruited immune cells, including: adipose tissue macrophages (ATMs, M2-alternative and M1-classically activated), eosinophils and type 2 innate lymphoid cells (ILC2) to stimulate WAT browning through commitment and differentiation of precursor cells at this site. The ability of M2-ATMs to produce catecholamines (tyrosine hydroxylase, TH) to sustain adaptive thermogenesis is under debate. Several stimuli have been reported to trigger or inhibit both mechanisms including among others stimulation by cold exposure and exercise, while others such as obesity and aging exert the opposite effect. Question marks depict mechanisms unknown or under debate. Methionine-enkephalin (MET-ENK).