Dysregulation of the adipoinsular axis - a mechanism for the pathogenesis of hyperleptinemia and adipogenic diabetes induced by fetal programming

Obesity and its related disorders are the most prevalent health problems in the Western world. Using the paradigm of fetal programming we developed a rodent model which displays the phenotype of obesity and metabolic disorder s commonly observed in human populations. We apply maternal undernutrition throughout gestation, generating a nutrient-deprived intrauterine environme nt to induce fetal programming. Maternal undernutrition results in fetal gr owth retardation and in significantly decreased body weight at birth. Progr ammed offspring develop hyperphagia, obesity, hypertension, hyperleptinemia and hyperinsulinism during adult life and postnatal hyper, caloric nutriti on amplifies the metabolic abnormalities induced by fetal programming. The adipoinsular axis has been proposed as a primary candidate for linking the status of body fat mass to the function of the pancreatic P-cells. We there fore investigated the relationship between circulating plasma concentration s of leptin and insulin and immunoreactivity in the endocrine pancreas for leptin and leptin receptor (OB-R) in genetically normal rats that were prog rammed to become obese during adult life. Virgin Wistar rats were time mate d and randomly assigned to receive food either available ad libitum (AD gro up) or at 30% of the ad libitum available intake (UN group). Offspring from UN mothers were significantly smaller at birth than AD offspring (AD 6(.)1 3 +/- 0(.)04 g, UN 4(.)02 +/- 0(.)03 g, P <0.001). At weaning, offspring we re assigned to one of two diets (a standard control diet or a hypercaloric diet consisting of 30% fat) for the remainder of the study. At the time of death (125 days of age), UN offspring had elevated (P <0(.)005) fasting pla sma insulin (AD control 1(.)417 +/-0(.)15 ng/ml, UN control 2(.)493 +/- 0(. )33 ng/ml, AD hypercaloric 1(.)70 +/- 0(.)17 ng/ml, UN hypercaloric 2(.)608 +/- 0(.)41 ng/ml)) and leptin (AD control 8(.)8 +/- 1(.)6 ng/ml, UN contro l 14(.)32 +/- 1(.)9 ng/ml, AD hypercaloric 15(.)11 +/- 1(.)8 ng/ml, UN hype rcaloric 30(.)18 +/- 5(.)3 ng/ml) concentrations, which vv,ere further incr eased (P <0(.)05) by postnatal hypercaloric nutrition. The elevated plasma insulin and leptin concentrations were paralleled by increased immunolabeli ng for leptin in the peripheral cells of the pancreatic islets. Dual immuno fluorescence histochemistry for somatostatin and leptin revealed that lepti n was co-localized in the pancreatic delta -cells. OB-R, immunoreactivity w as evenly distributed throughout the pancreatic islets and was not changed by programming nor hypercaloric nutrition. Our data suggest that reduced su bstrate supply during fetal development can trigger permanent dysregulation of the adipoinsular feedback system leading to hyperleptinemia, hyperinsul inism and compensatory, leptin production by pancreatic delta -cells in a f urther attempt to reduce insulin hypersecretion in the progression to adipo genic diabetes.