Second messenger signaling mechanisms of the brown adipocyte thermogenic program: an integrative perspective

Abstract

β-adrenergic receptors (βARs) are well established for conveying the signal from catecholamines to adipocytes. Acting through the second messenger cyclic adenosine monophosphate (cAMP) they stimulate lipolysis and also increase the activity of brown adipocytes and the 'browning' of adipocytes within white fat depots (so-called 'brite' or 'beige' adipocytes). Brown adipose tissue mitochondria are enriched with uncoupling protein 1 (UCP1), which is a regulated proton channel that allows the dissipation of chemical energy in the form of heat. The discovery of functional brown adipocytes in humans and inducible brown-like ('beige' or 'brite') adipocytes in rodents have suggested that recruitment and activation of these thermogenic adipocytes could be a promising strategy to increase energy expenditure for obesity therapy. More recently, the cardiac natriuretic peptides and their second messenger cyclic guanosine monophosphate (cGMP) have gained attention as a parallel signaling pathway in adipocytes, with some unique features. In this review, we begin with some important historical work that touches upon the regulation of brown adipocyte development and physiology. We then provide a synopsis of some recent advances in the signaling cascades from β-adrenergic agonists and natriuretic peptides to drive thermogenic gene expression in the adipocytes and how these two pathways converge at a number of unexpected points. Finally, moving from the physiologic hormonal signaling, we discuss yet another level of control downstream of these signals: the growing appreciation of the emerging roles of non-coding RNAs as important regulators of brown adipocyte formation and function. In this review, we discuss new developments in our understanding of the signaling mechanisms and factors including new secreted proteins and novel non-coding RNAs that control the function as well as the plasticity of the brown/beige adipose tissue as it responds to the energy needs and environmental conditions of the organism.

Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation

“…Apart from the classical interscapular BAT (iBAT), brown adipocytes are also present within specific white adipose tissues (WATs) (Frontini et al, 2013). These cells, morphologically resembling brown adipocytes, are referred to as brite or beige adipocytes, and their formation can be induced by certain environmental, hormonal, and pharmacological stimuli (Frontini et al, 2013;Rosenwald et al, 2013;Shi and Collins, 2017). Under specific conditions, physiologically relevant amounts of BAT can be found also in adult humans (Cypess et al, 2009;Nedergaard et al, 2007;van Marken Lichtenbelt et al, 2009).…”

Influence of Intermittent Cold Stimulations on CREB and Its Targeting Genes in Muscle: Investigations into Molecular Mechanisms of Local Cryotherapy

“…Sympathetic nerves were not stimulated. In response to cold exposure, the sensory nerves in peripheral tissues transduce the signal to the hypothalamus which regulates the sympathetic nervous system (SNS) and triggers the release of noradrenalin (NE) from the nerve terminals whence it enters the target tissue [24]. NE binds to the βadrenergic receptor (β-AR) and activates downstream signals including the production of cyclic AMP (cAMP), activation of protein kinase A (PKA), phosphorylation of CREB, upregulation of Pgc1-α, uncoupling of protein 1 (Ucp1), etc.…”

Estrogen receptor inhibition enhances cold-induced adipocyte beiging and glucose sensitivity

“…This unknown downstream signaling is yet to be elucidated, however, our preliminary findings indicated upregulated cAMP levels, which are a driving force in beiging, as well as an increased AdRβ3 expression. Although AdRβ3 signaling triggers prominent beiging 13,31,42 , AdRβ3-KO mice and mice treated with AdRβ3 antagonist display normal cold-induced beiging 43,44 , suggesting AdRβ3 is redundant in the specific response to cold-exposure. The findings in this study are not contradictory, since they propose that following ERα inhibition, brown/beige adipocytes are more sensitive to activationeither by cold-exposure or by AdRβ3 agonist.…”

“…Based on our observations, estrogen receptor inhibition enhanced cold-induced beiging. Adipocyte beiging is associated with multiple signaling pathways, predominantly cAMP-mediated pathways 31 . Indeed, Fulvestrant treatment in vitro elevated basal cAMP levels in differentiated beige cells and Forskolin-induced cAMP levels in undifferentiated cells ( Fig.…”

“…S9a), suggesting ERα inhibition "primes" cells to beiging. One of the key stimulants of cAMP-mediated signaling in adipocytes is the sympathetic nervous system, primarily via β-adrenoreceptors 9,13,31 .…”