Uncovering the Role of p38 Family Members in Adipose Tissue Physiology

Abstract

The complex functions of adipose tissue have been a focus of research interest over the past twenty years. Adipose tissue is not only the main energy storage depot, but also one of the largest endocrine organs in the body and carries out crucial metabolic functions. Moreover, brown and beige adipose depots are major sites of energy expenditure through the activation of adaptive, non-shivering thermogenesis. In recent years, numerous signaling molecules and pathways have emerged as critical regulators of adipose tissue, in both homeostasis and obesity-related disease. Among the best characterized are members of the p38 kinase family. The activity of these kinases has emerged as a key contributor to the biology of the white and brown adipose tissues, and their modulation could provide new therapeutic approaches against obesity. Here, we give an overview of the roles of the distinct p38 family members in adipose tissue, focusing on their actions in adipogenesis, thermogenic activity, and secretory function.

Keywords: Adipose; Brown; P38; kinase; p38 mitogen-activated protein kinase(s); signaling.

Figure 1

Role of p38 in WAT adipogenesis. In Myf5^- MSC cells, p38 protein kinase family members are activated by a variety of upstream activators, including BMP2–TAK1–MKK3/6, BMP4–FAK, and MCP1–MCPIP. p38-mediated phosphorylation and activation of CREB and ATF2 then leads to increased expression of Pparg2 and WAT adipogenesis. Solid arrows represent the direct effects of molecular players involved in the indicated signaling pathways, while dotted arrows represent indirect effects, meaning that other unknown molecules might be involved. ATF2, activating transcription factor 2;BMP, bone morphogenetic proteins; CREB, cAMP response element-binding; ER, endoplasmic reticulum; FAK, focal adhesion kinase; MCP1, monocyte chemotactic protein 1; MCPIP, MCP1-induced protein; MKK, mitogen-activated protein kinase kinase; ROS, reactive oxygen species; MSC, mesenchymal stem cell; Pparg2, peroxisome proliferator-activated receptor gamma 2; TAK1, transforming growth factor beta-activated kinase 1; WAT, white adipose tissue. Yellow circled ‘P’ indicates phosphorylation.

Figure 2

The p38 kinase family controls BAT adipogenesis. Brown adipocytes originate from Myf5⁺ MSC cells. BMP7 and Wnt3 activate p38 protein kinases, which phosphorylate and activate CREB and ATF2, leading to increased gene expression of brown adipocyte signature markers and mitochondrial biogenesis. p38δ has been suggested as the main kinase promoting BAT activation, whereas p38α has opposing effects. Black arrows represent the direct effects of molecular players involved in the indicated signaling pathways or effects. ATF2, activating transcription factor 2; BAT, brown adipose tissue; BMP, bone morphogenetic protein; C/ebp, CCAAT/enhancer-binding protein; CREB, cAMP response element-binding; MSC, mesenchymal stem cell; Ppargc1a, peroxisome proliferator-activated receptor gamma coactivator 1α; Prdm16, PR domain containing 16; Pparg, peroxisome proliferator-activated receptor; Ucp1, uncoupling protein 1. Yellow circled ‘P’ indicates phosphorylation.

Figure 3

Simplified scheme of the signaling cascade for BAT activation in response to cold. Cold-induced release of catecholamines by the SNS activates thermogenesis in brown adipocytes by stimulating β3-adrenergic receptors, which trigger PKA activation through an increase in intracellular cAMP. PKA participates in the activation of several transcription factors involved in the BAT thermogenic response. p38-mediated phosphorylation of several of these transcription factors is necessary for the expression of BAT signature genes. Solid arrows represent the direct effects of molecular players involved in the indicated signaling pathways, dotted arrows represent indirect effects, meaning that other unknown molecules might be involved, while red arrows represent translocation between cell compartments. AC, adenylyl cyclase; ATF2, activating transcription factor 2; cAMP, cyclic AMP; CREB, cAMP response element-binding; HSL, hormone sensitive lipase; PGC1α/Ppargc1a, peroxisome proliferator-activated receptor gamma coactivator 1α; PKA, protein kinase A; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; SNS, sympathetic nervous system; TAG, triglycerides; UCP1, uncoupling protein 1. Yellow circled ‘P’ indicates phosphorylation.

Figure 4

p38-signaling in white adipose tissue browning. WAT browning can be triggered by a variety of stimuli that converge on p38 signaling. In response to cold, hormones, drugs, or naturally occurring compounds, the SNS releases catecholamines to induce WAT browning by stimulating β3-adrenergic receptors. The ensuing PKA activation in turn activates p38. p38 phosphorylation and activation can alternatively be triggered by other molecules, such as cardiac NP acting via PKG, T3 hormone via an alternative pathway, or irisin released by skeletal muscle. Solid arrows represent the direct effects of molecular players involved in the indicated signaling pathways, while dotted arrows represent indirect effects, meaning that other unknown molecules might be involved. Active p38 phosphorylates the transcription factor ATF2, which translocates to the nucleus and upregulates the transcription of UCP1 and other key genes essential for transforming white adipocytes into beige adipocytes. AC, adenylate cyclase; AMPK, AMP-activated protein kinase; ATF2, activating transcription factor 2; cAMP, cyclic AMP; GC, guanylate cyclase; cGMP, cyclic GMP; CREB, cAMP response element-binding; MKK6, mitogen-activated protein kinase kinase 6; NP, natriuretic peptides; PGC1α/Ppargc1a, peroxisome proliferator-activated receptor gamma coactivator 1α; PKA, protein kinase A; PKG, protein kinase G; PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X receptor; SNS, sympathetic nervous system; TAB1, TAK1 binding protein 1; TAK1, transforming growth factor beta-activated kinase 1; Ucp1, uncoupling protein 1. Yellow circled ‘P’ indicates phosphorylation.

Figure 5

The p38-mediated adipose tissue secretome. The p38 pathway controls the expression or secretion of distinct adipokines in WAT and BAT. In white adipocytes, p38 activation is required for the production of IL6, PAI-1, and Wdnm1-like after TNFα stimulation. p38 signaling also controls leptin secretion in response to TNFα, playing a positive role in the presence of dexamethasone, but an inhibitory role in response to alamandin. p38 is also involved in the secretion of IL6 in response to amlexanox and in the induction of PAI-1 after β3AR stimulation. In brown adipocytes, p38 controls the secretion of FGF21 induced by NE, GW9805, or EPA and directs the secretion of CXCL14 after cAMP stimulation. cAMP, cyclic AMP; EPA, eicosapentanoic acid; FGF21, fibroblast growth factor 21; IL6, interleukin-6; NE, norepinephrine; PAI-1, plasminogen activator inhibitor-1; TNFα, tumor necrosis factor α.