Molecular Mechanisms of Adipogenesis: The Anti-adipogenic Role of AMP-Activated Protein Kinase

Abstract

Obesity is now a widespread disorder, and its prevalence has become a critical concern worldwide, due to its association with common co-morbidities like cancer, cardiovascular diseases and diabetes. Adipose tissue is an endocrine organ and therefore plays a critical role in the survival of an individual, but its dysfunction or excess is directly linked to obesity. The journey from multipotent mesenchymal stem cells to the formation of mature adipocytes is a well-orchestrated program which requires the expression of several genes, their transcriptional factors, and signaling intermediates from numerous pathways. Understanding all the intricacies of adipogenesis is vital if we are to counter the current epidemic of obesity because the limited understanding of these intricacies is the main barrier to the development of potent therapeutic strategies against obesity. In particular, AMP-Activated Protein Kinase (AMPK) plays a crucial role in regulating adipogenesis - it is arguably the central cellular energy regulation protein of the body. Since AMPK promotes the development of brown adipose tissue over that of white adipose tissue, special attention has been given to its role in adipose tissue development in recent years. In this review, we describe the molecular mechanisms involved in adipogenesis, the role of signaling pathways and the substantial role of activated AMPK in the inhibition of adiposity, concluding with observations which will support the development of novel chemotherapies against obesity epidemics.

Keywords: AMPK; BAT; WAT; adipogenesis; beige/brite adipocytes; obesity.

FIGURE 1

Differentiation of MSCs into white, beige/brite and brown adipocytes. Myf-5, Myogenic Factor-5 protein; BMP 7, Bone morphogenetic protein 7; BMP 2, Bone morphogenetic protein 2; BMP 4, Bone morphogenetic protein 4; PRDM 16, PR-domain containing 16; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PPARγ, peroxisome proliferator-activated receptor gamma; PTEN, phosphatase and tensin homologue; C/EBPα,β,δ, CCCAAT/Enhancer Binding Protein α, β, δ.

FIGURE 2

Transcriptional regulation of adipogenesis. Arrows represent activation and bars represent inhibition. MSCs, mesenchymal stem cells; DNA, deoxyribonucleic acids; C/EBPs, CCAAT/enhancer binding proteins. C/EBPβ,δ; CCCAAT/Enhancer Binding Protein β, δ, KLF 4,5,6,9,13,15, Kruppel-like factor 4,5,6,9,13,15; SREBP-1, Sterol regulatory binding protein-1; KLF 2,3,7,16, Kruppel-like factor 2,3,7,16; GATA 2,3, GATA binding protein 2,3; EBF-1, 2, Early β-cell factor 1,2; CREB, cyclic AMP response binding element; PREF-1, preadipocyte factor-1; pRb, retinoblastoma protein; FAS, fatty acid synthase; ACC, acetyl CoA carboxylase; FABP-4, fatty acid binding protein-4.

FIGURE 3

A schematic diagram of the TGF-β and BMPs pathway. TGF-β, transforming growth factor-beta; TGF-β-R1,2, transforming growth factor-beta receptor type 1, 2; co-SMAD, common-SMAD; BMPs, bone morphogenetic proteins; BMP-R1,2, bone morphogenetic protein- type 1 and 2 receptors.

FIGURE 4

Inhibition of adipogenesis through Wnt/β catenin dependent pathway. Arrows indicate activation and bars indicate inhibition. LRP 5/6, lipoprotein receptor-related protein 5/6; GSK-3, glycogen synthase kinase-3; APC, adenomatous polyposis coli;TCF/LEF, T-cell factors/lymphoid-enhancing factor; PPARγ, peroxisome proliferator-activated receptor gamma; C/EBPα, CCCAAT/Enhancer Binding Protein alpha; FAS, fatty acid synthase; aP2, adipocyte fatty acid binding protein.

FIGURE 5

Mechanism of action of Hedgehog signaling pathway. Hh, Hedgehog protein; DISP, dispatched protein; PTCH, patched protein; SMO, Smoothened protein; Gli 1,2,3, glioblastoma gene 1,2,3.

FIGURE 6

Activation and functions of AMPK in adipose tissue. Orange arrow and bar indicates functions of ACC and MCoA in the absence of AMPK activation. Arrows indicate activation and bars indicate inhibition. ACC, acetyl-CoA carboxylase; MCoA, malonyl co-enzyme A; CPT1, carnitine palmitoyltransferase 1; CaMKK2, calcium/calmodulin-dependent protein kinase kinase 2; LKB1, liver kinase b1; ULK1, Unc-51 Like Autophagy Activating Kinase 1; UCP1, uncoupling protein 1; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; SREBP-1c, sterol regulatory element binding protein 1; C/EBPα, CCCAAT/Enhancer Binding Protein alpha; PPARγ, Peroxisome proliferator-activated receptor gamma.