SIRT1 Limits Adipocyte Hyperplasia through c-Myc Inhibition

Abstract

The expansion of fat mass in the obese state is due to increased adipocyte hypertrophy and hyperplasia. The molecular mechanism that drives adipocyte hyperplasia remains unknown. The NAD+-dependent protein deacetylase sirtuin 1 (SIRT1), a key regulator of mammalian metabolism, maintains proper metabolic functions in many tissues, counteracting obesity. Here we report that differentiated adipocytes are hyperplastic when SIRT1 is knocked down stably in mouse 3T3-L1 preadipocytes. This phenotype is associated with dysregulated adipocyte metabolism and enhanced inflammation. We also demonstrate that SIRT1 is a key regulator of proliferation in preadipocytes. Quantitative proteomics reveal that the c-Myc pathway is altered to drive enhanced proliferation in SIRT1-silenced 3T3-L1 cells. Moreover, c-Myc is hyperacetylated, levels of p27 are reduced, and cyclin-dependent kinase 2 (CDK2) is activated upon SIRT1 reduction. Remarkably, differentiating SIRT1-silenced preadipocytes exhibit enhanced mitotic clonal expansion accompanied by reduced levels of p27 as well as elevated levels of CCAAT/enhancer-binding protein β (C/EBPβ) and c-Myc, which is also hyperacetylated. c-Myc activation and enhanced proliferation phenotype are also found to be SIRT1-dependent in proliferating mouse embryonic fibroblasts and differentiating human SW872 preadipocytes. Reducing both SIRT1 and c-Myc expression in 3T3-L1 cells simultaneously does not induce the adipocyte hyperplasia phenotype, confirming that SIRT1 controls adipocyte hyperplasia through c-Myc regulation. A better understanding of the molecular mechanisms of adipocyte hyperplasia will open new avenues toward understanding obesity.

Developmental Stage, Muscle and Genetic Type Modify Muscle Transcriptome in Pigs: Effects on Gene Expression and Regulatory Factors Involved in Growth and Metabolism

“…Common genes identified by the different followed procedures were of special interest. Specifically, HSF1 , JARID2 , TCF4 and YBX3 play known roles in muscle development and protein metabolism [70–74], while TFEB and MYC are involved in adipocyte proliferation, lipid metabolism and fatty acid transport [75, 76]. These TRF potentially regulate muscle and fat accretion in young pigs and are thus, of special interest in the understanding of molecular mechanisms underlying such processes in pigs and other species.…”

Adipose tissue NAD+ biology in obesity and insulin resistance: From mechanism to therapy

“…Indeed, adipocyte‐specific Nampt deletion also causes macrophage infiltration in adipose tissue , suggesting the important role of NAMPT‐NAD + ‐SIRT1 as a negative regulator of macrophage activation, a key feature that contributes to the development of obesity‐associated insulin resistance. Recently, it was also reported that SIRT1 inhibits adipocyte hyperplasia though the deacetylation of Lys323 on c‐Myc . Finally, it should be noted that SIRT1 enhances the enzymatic activity and secretion of eNAMPT by deacetylating Lys53 on NAMPT, thus affecting hypothalamic function and physical activity .…”

Mitochondrial Dysfunction in Age‐Related Metabolic Disorders

“…[ 122–125 ] High levels of SIRT1 were also observed in hyperplasia of adipocytes indicating its necessity in regulating adipose tissue function. [ 126 ] AMPK and SIRT modulate peroxisome proliferator‐activated receptor gamma coactivator 1α (PGC1α), a central factor regulating mitochondrial biogenesis and gene copy number thus modulating oxidative phosphorylation. [ 127,128 ] However, association of AMPK, SIRT, and mTOR dysfunction with metabolic disorder in aged tissues remains poorly understood.…”