Abstract
Besides its role as a cell cycle and proliferation regulator, the INK4a/ARF (CDKN2A) locus and its associated pathways are thought to play additional functions in the control of energy homeostasis. Genome-wide association studies in humans and rodents have revealed that single nucleotide polymorphisms in this locus are risk factors for obesity and related metabolic diseases including cardiovascular complications and type-2 diabetes (T2D). Recent studies showed that both p16INK4a-CDK4-E2F1/pRB and p19ARF-P53 (p14ARF in humans) related pathways regulate adipose tissue (AT) physiology and adipocyte functions such as lipid storage, inflammation, oxidative activity, and cellular plasticity (browning). Targeting these metabolic pathways in AT emerged as a new putative therapy to alleviate the effects of obesity and prevent T2D. This review aims to provide an overview of the literature linking the INK4a/ARF locus with AT functions, focusing on its mechanisms of action in the regulation of energy homeostasis.
Highlights
The global epidemic of obesity and associated metabolic diseases have increased substantially over the past decades
The cyclin-dependent kinase 4 (CDK4) which mediates the phosphorylation of phosphorylation of Rb family members (pRB) resulting in the dissociation of E2F1 and activation of the cell-cycle progression from G1 to S phase (Figure 1) is a key molecule involved in adipocyte insulin sensitivity
In support of this notion, we showed that CDKN2A-deficient mice were protected against diet-induced obesity (DIO) exhibiting subcutaneous WAT (sWAT) browning and increased thermogenesis and insulin sensitivity [60]
Summary
The global epidemic of obesity and associated metabolic diseases have increased substantially over the past decades. Biomolecules 2020, 10, 1350 can be seen as an accelerated form of AT senescence [63] In both cases, cell senescence characterized by elevated p16INK4a/p53 expression appears to be a key mechanism for reduced regenerative potential of adipose progenitor cells and impaired adipocyte replacement. It is tempting to speculate that epigenetic mechanisms regulating differentiation transcriptional program may account for the adipose stem cell fate decision between senescence and differentiation in obese individuals These findings are in line with the AT expandability theory which proposes that the inability of further AT expansion in obese individuals is a key determinant of dysfunctional AT, inflammation, and insulin resistance [65]. The cyclin-dependent kinase 4 (CDK4) which mediates the phosphorylation of pRB resulting in the dissociation of E2F1 and activation of the cell-cycle progression from G1 to S phase (Figure 1) is a key molecule involved in adipocyte insulin sensitivity. KFi4nmalluyt,atnrtehaatmveeinntcorefa3sTe3d-bLo1daynwdehiguhmt,afnatamdiapsos,cayntedslawrigtehrpad53ip-ioncdyutecser[6s8d].oAxosrsutrboicnign e(avidDeNncAe odfaimts acgeell--ianudtuocnionmg odursuagc)tioannd, CnDuKtl4inw-3aas srheodwucnesto iancstuivliant-esttihmeuinlastueldin-gsliugcnoasleingupptaatkhewabyy tlhorwoeurginhgphGoLsUpTh4orgylluatcioosne otfrainnssupolirnterrecterapntoslroscuabtisotnra. tTeh2is(IaRdSi2p)oactySteerc3e8l8l-auuptoonnoimnsouulisnesftfiemctuloactciounrs, tihnudsempeanindteanintliyngofininsufllainmamctaiotinoinn[a6d4i]p. oAclythteosu(g[5h5E],2FFig1uarned3)p. 5In3taerreestthinogulgyh, ItRtSo2i-nSteerr3a8c8t pwhiothspthheoriynlsautiloinnisnighnuamlinang vpWatAhTwiasypotositmivoedlyuclaotrereAlaTtedinwsuitlhinBMseInasintdivniteyg, aytievteltyhecourrnedlaetrelys iwngithmbelochodangislumcsosaerleevsetillsl iunnpcaletiaern. ts [55]
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