Impaired insulin and leptin sensitivity in the offspring of moderate caloric-restricted dams during gestation is early programmed ★

We aimed to assess the mechanisms responsible for hyperphagia and metabolic alterations caused by maternal moderate caloric restriction during gestation. Male and female offspring of control and 20% caloric-restricted rats (CR) were studied. They were fed a normal-fat diet until 4 months of age and then moved to a high-fat diet until 6 months of age. Blood parameters and expression of selected genes in hypothalamus, retroperitoneal white adipose tissue (rWAT) and liver were analyzed at 25 days and 6 months of age. Plasma leptin was measured during suckling. Levels of proteins involved in insulin and leptin signaling were determined at 6 months of age. CR ate more calories than controls, but only males gained more weight. A peak in plasma leptin was found in 9-day-old controls, but was absent in CR. Twenty-five-day-old CR showed lower insulin receptor mRNA levels in hypothalamus, rWAT and liver, and long-form leptin receptor (ObRb) in hypothalamus. At the age of 6 months, homeostatic model assessment for insulin resistance index was higher in CR than controls, and CR males also displayed hyperleptinemia. Adult CR also showed lower ObRb mRNA levels in the hypothalamus (only females, but both showed altered neuropeptide Y/proopiomelanocortin mRNA ratio), rWAT and liver (males), and a decrease of protein kinase C zeta levels in rWAT (females) and liver (males) and of phosphorylated signal transducer and activator of transcription 3 in liver (females). These results suggest that CR animals are programmed for insulin and central leptin resistance, which may explain the dysregulation of appetite and other metabolic alterations, favoring obesity development, although only manifested in males. These early programming effects could be associated with the absence of leptin surge during lactation.