The hypothalamus–adipose axis is a key target of developmental programming by maternal nutritional manipulation

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   Figure 1

   Schematic overview of the hypothalamus–adipose axis (based on rat data) involved in food intake regulation and energy expenditure. In short, the arcuate nucleus (Arc) integrates peripheral endocrine signal via blood (such as leptin). Leptin acts on its receptor to modulate the expression and release of Arc appetite-regulating neuropeptides. Then, the Arc drives other hypothalamic areas such as ventromedial (VMN), dorsomedial (DMN) and paraventricular (PVN) nuclei (considered as satiety centres) and the lateral hypothalamic area (LHA; considered as a hunger centre). Coronal section shows the relative position of these nuclei with respect to each other through the hypothalamus. Circuits allowing communications between these neuronal populations are indicated by red arrows. Neuronal signal, especially from the PVN, modulates via the nucleus of the solitary tract (NTS) located in the brainstem, the activity of sympathetic autonomic nervous system (indicated by a green arrow). Then, it regulates energy expenditure such as lipolysis and/or thermogenesis in adipose tissue.
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   Figure 2

   Schematic representation of leptin/insulin intracellular signalling pathways in the arcuate nucleus of hypothalamus. To simplify the figure, only factors that are primary targets of maternal nutrition manipulation have been represented. Leptin binding to its receptor (Ob-Rb) induces activation of JAK2, receptor dimerisation, JAK2-mediated phosphorylation of intracellular part of Ob-Rb, phosphorylation and activation of STAT3. Activated STAT3 dimerises and translocates to the nucleus to transactivate target genes. Modulation of gene expression is indicated by black arrows. Insulin binding to its receptor (InsR) induces receptor tyrosine autophosphorylation and activation of insulin receptor substrates (IRSs)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt/PKB) signalling pathways. Both hormones reduce the expression and release of orexigenic peptides such as neuropeptide Y (NPY)/agouti-related peptide (AgRP) and activate anorexigenic peptides such as α-melanocyte-stimulating hormone (α-MSH, a neuropeptide derived from pro-opiomelanocortin (POMC) processing in the hypothalamus)/cocaine- and amphetamine-regulated transcript (CART). Leptin also activates the expression of suppressors of cytokine signalling 3 (SOCS3) that in turn inhibits leptin-induced tyrosine phosphorylation of JAK2 and STAT3 activation (indicated in red). The direct cross talk between insulin and leptin signalling at the level of JAK2/IRSs/PI3K is represented. NPY that selectively binds to Y1 NPY receptor (Y1R) induces the expression and release of orexigenic peptides (i.e. orexins and melanin concentrating hormone (MCH) in the lateral hypothalamic area) and decreases the expression and release of anorexigenic peptides (i.e. corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) in the paraventricular nucleus), thereby increasing food intake and decreasing energy expenditure. By contrast, α-MSH that binds to MC4 receptor (MC4R) acts on the opposite way, thereby decreasing food intake and increasing energy expenditure.
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   Figure 3

   Schematic representation of basic steps in lipogenesis and lipolysis in the adipocyte. To simplify the figure, only mechanisms that are primary targets of maternal nutrition manipulation have been represented. Triacylglycerol (TG) circulates in blood in the form of lipoproteins. Free fatty acids (FFA) that are released from lipoproteins, catalysed 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 by glucose metabolism. FFA 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 that hydrolyzes TG into FFA and glycerol. These FFA are then free to diffuse into the blood. Insulin enhances the storage of fat as TG by increasing LPL and lipogenic enzyme activities. It also facilitates the transport of glucose by stimulating the 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 levels in adipocytes. By contrast, leptin presents antilipogenic and lipolytic effects by suppressing expression and activity of lipogenic enzymes and PPARG. Noradrenaline released from the sympathetic autonomic nervous system binds β-adrenoreceptor (β-AR) and activates lipolysis. Prolonged exposure to glucocorticoids (GC) that bind intracellular glucocorticoid receptor (GR) enhances adipogenesis. This may be due either to an increase in circulating GC and/or to an increase in intracellular 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity that predominantly converts inactive cortisone to active corticosterone, thus amplifying local GC action.
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   Figure 4

   Schematic overview of the long-lasting effects of maternal nutritional manipulation on the hypothalamus–adipose tissue axis in the offspring. In most cases, animals display hyperleptinaemia, hypothalamic leptin resistance, impaired leptin receptor signalling pathways and enhanced orexigenic pathways (especially NPY) leading to hyperphagia. Offspring also show reduced sympathetic autonomic nervous system innervation, impaired sympathetic outflow activity and modified ratio of adrenoreceptor subtypes. These may affect adipose tissue functions (i.e. higher fat cell proliferation and lipogenesis as well as lower lipolysis and thermogenesis) sensitising to fat mass accumulation. Overall, higher energy intake, altered sympathetic activity and global increased adipogenesis and/or lipogenesis capacities may promote offspring obesity.

• © 2013 Society for Endocrinology