Emerging Roles for the INK4a/ARF (CDKN2A) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes

Figures

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  Figure 1. The INK4a/ARF locus. The INK4a/ARF locus is located on chromosome 9p21 in humans and chromosome 4 in rodents. It encodes for two proteins, p16INK4a the principal member of the INK4 family of cyclin-dependent kinase inhibitors (CDKI) and the p53 regulatory protein p14ARF (p19ARF in mice). Both are key regulators of the cell cycle machinery with an anti-proliferative and tumor suppressor role. p16INK4a binds to CDK4/6, inhibiting cyclin D-CDK4/6 complex formation and CDK4/6-mediated phosphorylation of Rb family members (pRB). Expression of p16INK4a maintains pRB in a hypophosphorylated state, which promotes binding to the transcription factors E2F and blocks the passage of the G1 to S phase. p14ARF (p19ARF in mice) mainly exerts its anti-proliferative activity via the inhibition of the mouse double minute 2 homolog (MDM2), an ubiquitin-ligase that hampers the activity of the transcription factor p53, acting as a tumor suppressor, blocking cells in G1 and G2 phase.

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  Figure 2. The INK4a/ARF locus as a key regulatory hub to maintain adipose tissue in a healthy state. The INK4A/ARF locus regulates the balance between adipogenesis and senescence and promotes lipid storage as triglycerides and adipocyte hypertrophy via the insulin-signaling pathway. It has been described as a molecular switch of white-to-beige adipocyte conversion and as a key determinant of brown adipocyte fate, being an alternative way to increase energy expenditure. It is also involved in the switch between macrophage phenotype and thus obesity-related inflammation.

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  Figure 3. The INK4a/ARF locus modulates the insulin-signaling pathway in adipocyte. Insulin attaches to insulin receptor triggering intracellular autophosphorylation of their tyrosine residues, which constitutes an attachment for insulin receptor substrate (IRS) proteins. These molecules undergo phosphorylation and form a complex with PI3K. PI3K phosphorylates PIP2, which results in PIP3 formation and activation of PDK1. AKT gets phosphorylated and activated by PDK1. The latter is responsible for GLUT4 translocation to cellular membrane and glucose inflow. CDK4 was shown to activate the insulin-signaling pathway through phosphorylation of IRS2 at Ser388 upon insulin stimulation, thus maintaining insulin action in adipocytes. Although E2F1 and p53 are thought to interact with the insulin-signaling pathway to modulate AT insulin sensitivity, yet the underlying mechanisms are still unclear.

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  Figure 4. The INK4a/ARF locus: an emerging key actor in metabolic functions. In addition to AT, the INK4A/ARF (CDKN2A) locus is thought to play a variety of role in metabolic functions under normal and physiopathological conditions in other organs (pancreas, liver, muscle, heart, and brain). This locus affects glucose homeostasis, β-cell functions and mass, hepatic gluconeogenesis and lipid storage as well as cardiovascular functions. It also regulates the circadian rhythm, neurogenesis, and axonal regeneration.