Programming of the Adipoinsular Axis and Altered Adipogenesis

It is important to note that very few animal studies have addressed interactions between pre and postnatal nutrition. However, other studies that have investigated diet-induced obesity point to a link between peripheral leptin resistance and insulin resistance in the development of obesity. The physiological role of hyperleptinemia associated with caloric excess has been proposed to relate to the protection of nonadipocytes from lipid oversupply that would lead to steatosis and lipotoxicity.68 Elevated leptin production as a result of short-term caloric excess prevents the up-regulation of lipogenesis and increases fatty acid oxidation, thus reducing lipid supply to peripheral tissue during caloric excess.68 In diet-induced obesity, peripheral leptin function is at first normal. However, prolonged caloric excess results in dysregulation of post-receptor leptin signalling. This causes accumulation of triglycerides and lipid metabolites, providing fatty acid substrate for the damaging effects of nonoxidative metabolism leading to functional impairment of nonadipose tissue and a progression to type 2 diabetes and cardiovascular disease.

A range of genetic components of obesity have been identified.70"72 and research on alterations in biochemical pathways caused by single gene mutations in animal models has contributed significandy towards knowledge of physiological mechanisms of obesity.73 It is well established that leptin acts at the level of the hypothalamus to regulate appetite and energy homeostasis. The long-form, or signalling form, of the leptin receptor (OB-Rb) is expressed in high levels in several cell groups of the hypothalamus and in various tissues throughout the body.48'75'76 Under normal physiological conditions, increased leptin signalling in the medial hypothalamus is associated with reduced neuropeptide Y (NPY) and agouti-related (AgRP) protein production77 but increased cocaine- and amphetamine- regulated transcript (CART) and pro-opiomelanocortin (POMC) production.7 These leptin-induced changes in neuropeptides lead to decreased food intake and increased energy expenditure.

In obese individuals, elevated plasma leptin is proposed to uncouple leptin action on its receptors in the hypothalamus, thereby disrupting signal transduction pathways that exert effects on satiety and energy expenditure.74 Direct leptin signalling in peripheral tissues has only recendy been demonstrated. For example, increased leptin signalling in muscle tissue has been shown to blunt lipogenesis and stimulate lipid oxidation.81 There is also growing evidence for a feedback system between leptin and insulin which links the brain and the endocrine pancreas with other peripheral insulin and leptin sensitive tissues in the control of feeding behaviour, metabolic regulation and body energy balance.82 This endocrine system has been termed the adipoinsular axis.82 When adipose stores decrease, falling leptin concentrations permit increased insulin production resulting in the deposition of additional fat. Conversely the suppressive effects of leptin on insulin production is mediated by the autonomic nervous system and by direct actions via leptin receptor on beta-cells.82 Our data suggest that fetal programming by maternal undernutrition throughout gestation may lead to dysregulation of the adipoinsular feedback system. Relative leptin resistance by pancreatic (3—cells may contribute to hyperin-sulinism which further exacerbates adipogenesis. The hyperinsulinism and hyperleptinemia may also trigger the pathogenesis of hyperphagia.

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