Hypothalamic systems which regulate appetite may be permanently modified during early development. We have previously reported hyperphagia and increased adiposity in the adult offspring of rodents fed an obesogenic diet prior to and throughout pregnancy and lactation. We now report that offspring of obese (OffOb) rats display an amplified and prolonged neonatal leptin surge, which is accompanied by elevated leptin mRNA expression in their abdominal white adipose tissue. At postnatal Day 30, before the onset of hyperphagia in these animals, serum leptin is normal, but leptin-induced appetite suppression and phosphorylation of STAT3 in the arcuate nucleus (ARC) are attenuated; the level of AgRP-immunoreactivity in the hypothalamic paraventricular nucleus (PVH), which derives from neurones in the ARC and is developmentally dependent on leptin, is also diminished. We hypothesise that prolonged release of abnormally high levels of leptin by neonatal OffOb rats leads to leptin resistance and permanently affects hypothalamic functions involving the ARC and PVH. Such effects may underlie the developmental programming of hyperphagia and obesity in these rats.

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Abstract-Maternal obesity in rodents is associated with increased adiposity, impaired glucose tolerance, and hypertension in adult offspring. In this study we investigated the influence of maternal obesity in the rat on blood pressure and blood pressure regulatory pathways in juvenile and adult offspring. Obesity was induced before pregnancy in female Sprague-Dawley rats by feeding a highly palatable energy-dense diet. In juvenile animals (30 days of age), before the onset of obesity and hyperleptinemia, basal nighttime mean arterial pressure was significantly raised in the offspring of obese dams (OffOb) relative to offspring of controls (OffCon; mean arterial pressure, males: OffOb, 121.8Ϯ0.6 mm Hg versus OffCon, 115.0Ϯ0.5 mm Hg, nϭ6, PϽ0.01; females: OffOb, 125.4Ϯ0.4 mm Hg versus OffCon, 114.4Ϯ0.5 mm Hg, nϭ6, PϽ0.001), as was the mean arterial pressure response to restraint stress (PϽ0.01). The pressor response to a leptin challenge was enhanced in OffOb rats (⌬mean arterial pressure: OffOb, 9.7Ϯ0.8 mm Hg versus OffCon, 5.3Ϯ1.3 mm Hg; nϭ8; PϽ0.05). Renal tissue norepinephrine content (PϽ0.001) and renin expression (PϽ0.05) were markedly raised. Analysis of heart rate variability revealed an increased low:high frequency ratio in OffOb versus OffCon rats (PϽ0.05). At 90 days, hypertension in OffOb rats persisted and was abolished by ␣1-and ␤-adrenergic blockade, and cardiovascular responses to phenylephrine or sodium nitroprusside indicated altered baroreceptor function. The exaggerated pressor response to leptin in OffOb rats was maintained. Hypertension in the offspring of obese rats may arise from persistent sympathoexcitatory hyperresponsiveness acquired in early stages of development. (Hypertension. 2010;55:76-82.)Key Words: hypertension Ⅲ sympathetic activity Ⅲ leptin Ⅲ developmental programming Ⅲ kidney T he influences of the worldwide obesity epidemic on reproductive health in women, particularly in relation to an adverse pregnancy outcome, present a significant health burden and a substantive healthcare cost. 1 We now appreciate that consequences for the child may extend well beyond the perinatal period. Evidence from observational cohort studies has suggested that maternal obesity is an independent determinant of childhood obesity and metabolic syndrome, arising from adverse influences of the maternal "hypernutritional" environment on the developing child; however, because of a multiplicity of confounding variables, causality cannot easily be proven. 2-5 Studies on experimental animals have provided the strongest evidence for a causal relationship. 2,6 -8 We have developed a rodent model of maternal obesity in mice 9 and rats 6 and have shown that adult offspring display many features of the metabolic syndrome, including hypertension at 3 months of age. 9 We reported recently that hyperphagia and increased adiposity in adult rat offspring are associated with resistance to the anorectic and weight-reducing actions of leptin, as well as impaired leptin signaling in the arcuate nucleus of the hypothala...

The mechanisms underlying weight gain resulting from antipsychotic drugs are not fully understood, although antagonism of the 5-HT2C receptor is likely to contribute. Animal studies indicate that the drugs most likely to cause weight gain, clozapine and olanzapine, have direct effects on the NPY-containing neurons of the hypothalamus; these neurons mediate the effects of the circulating anorexigenic hormone leptin on the control of food intake. The substantial differences between individuals in the extent of antipsychotic-induced weight gain suggest that genetic factors may be important. We have been studying pharmacogenetic correlates and find that a common 5-HT2C receptor promoter region polymorphisms demonstrates strong associations with weight gain in two first episode psychotic samples. In both series, we have found further association of antipsychotic drug-induced weight gain with a common and functional polymorphism of the gene for leptin. Along with initial BMI, these two pharmacogenetic factors account for almost 30% of the variance in drug-induced weight gain. Interestingly, the 5-HT2C polymorphism appears to determine levels of circulating leptin, providing a potential mechanism underlying the genetic association of the 5-HT2C receptor with weight gain. We have undertaken functional studies of haplotypes of the 5-HT2C promoter region and find the allele associated with protection from weight gain results in reduced promoter activity. These findings demonstrate the value of pharmacogenetics in determining liability to a major side effect of antipsychotic treatment, and indicate both the molecular and physiological mechanisms underlying this side effect.

These results suggest that 5-HT2C receptor antagonism or inverse agonism, in the presence of D2 receptor antagonism, may contribute to olanzapine-induced weight gain.