The cellularity of offspring's adipose tissue is programmed by maternal nutritional manipulations

Figures & data

Figure 1. Intracellular pathways of factors regulating adipogenesis, lipogenesis and lipolysis in the adipocyte. To simplify, only mechanisms that are primary targets of maternal nutrition manipulations have been represented. Triglycerides (TG) circulate in blood in the form of lipoproteins. Free fatty acids (FFA) that are released from lipoproteins, catalyzed by lipoprotein lipase (LPL), diffuse into the adipocyte. Intracellular FFA are converted to fatty acyl-CoA, and are then re-esterified to form TG using glycerol-3 phosphate (glycerol-3P) that is generated from glucose metabolism. FFAs may also originate from acetyl-CoA (de novo lipogenesis) driven by the lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Lipolysis occurs via a cAMP-mediated cascade, which results in the phosphorylation of hormone-sensitive lipase (HSL), an enzyme which hydrolyzes TG into FFA and glycerol. These FFA are then free to diffuse into the blood. Leptin binding to its receptor (Ob-Rb) induces activation of Janus activated kinase 2 (JAK2), receptor dimerization, JAK2-mediated phosphorylation of intracellular part of Ob-Rb, phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3). Activated STAT3 dimerizes and translocates to the nucleus to transactivate target genes. Insulin binding to its receptor (InsR) induces receptor tyrosine autophosphorylation, activation of insulin receptor substrates (IRSs)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt/PKB) signaling pathways. Leptin and insulin action is both linked to the common PI3K signaling pathway. Insulin enhances the storage of fat as TG by increasing LPL and lipogenic enzyme activities. It also facilitates the transport of glucose by stimulating GLUT4 glucose transporter. In addition, phosphorylation and activation of cyclic nucleotide phosphodiesterases 3B (PDE3B) is a key event in the antilipolytic action of insulin, decreasing cAMP level in adipocyte. In contrast, leptin presents anti-lipogenic effects by suppressing expression and activity of lipogenic enzymes (i.e., fatty acid synthase [FAS]). Both hormones may also activate adipogenesis. Adipogenesis is driven by the expression of adipogenic and lipogenic transcription factors including peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer binding protein (C/EBPα, β, γ), the sterol regulatory element-binding protein 1c (SREBP1c) as well as the expression of specific lipid-metabolizing enzymes such as FAS. Noradrenaline released from the sympathetic autonomic nervous system binds β-adrenoreceptor (β-AR) and activates lipolysis. Glucocorticoids (GC) bind intracellular glucocorticoid receptor (GR) and/or mineralocorticoid receptor (MR) and can also modulate adipogenesis and/or lipogenesis. This may be due either to an increase in circulating GC and/or to an increase in adipose tissue 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity that amplifies local GC actions by converting inactive GC metabolites (11-dehydrocorticosterone, 11DHC) to active GC (corticosterone) (in rodents) or inactive cortisone to active cortisol (in humans). 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) that degrades active GC to inactive metabolites is also found in adipose tissue.