We have previously described that neonate rats supplemented with physiological doses of oral leptin during lactation become more protected against overweight in adulthood. The purpose of this study was to characterize further the long-term effects on glucose and leptin homeostasis and on food preferences. Neonate rats were supplemented during lactation with a daily oral dose of leptin or the vehicle. We followed body weight and food intake of animals until the age of 15 months, and measured glucose, insulin, and leptin levels under different feeding conditions: ad libitum feeding, 14-h fasting, and 3-h refeeding after fasting. An oral glucose tolerance test and a leptin resistance test were performed. Food preferences were also measured. Leptin-treated animals were found to have lower body weight in adulthood and to eat fewer calories than their controls. Plasma insulin levels were lower in leptin-treated animals than in their controls under the different feeding conditions, as was the increase in insulin levels after food intake. The homeostatic model assessment for insulin resistance index was significantly lower in leptin-treated animals, and the oral glucose tolerance test also indicated higher insulin sensitivity in leptin-treated animals. In addition, these animals displayed lower plasma leptin levels under the different feeding conditions and were also more responsive to exogenous leptin administration. Leptin-treated animals also showed a lower preference for fat-rich food than their controls. These observations indicate that animals supplemented with physiological doses of oral leptin during lactation were more protected against obesity and metabolic features of the metabolic syndrome.

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The aim of this study was to provide a sequential analysis of the expression patterns of key genes involved in lipid metabolism in white adipose tissue (WAT) and liver and their relationship with blood parameters in response to fasting. Adult male rats were studied under different feeding conditions: feeding state, after 4, 8, or 24 h fasting, and after 3 h refeeding after 8 h fasting. Blood parameters and the expression of genes involved in lipogenesis and lipolysis in WAT and liver were analyzed. mRNA levels of genes involved in lipogenesis in liver (SREBP1c, FAS, and GPAT) had already decreased after 4 h fasting, as well as those of PPARgamma in WAT, whereas the decrease in SREBP1c, FAS, GPAT, and GLUT4 mRNA levels in WAT was observed after 8 h. Concerning lipolytic and fatty-acid-oxidation-related genes, liver PPARalpha, FGF21, CPT1, and PDK4 mRNA levels increased after 8 h fasting and those of ACOX1 after 24 h, and in WAT, ATGL, and CPT1 mRNA levels were greater after 24 h. Three hours refeeding increased the expression levels of PPARgamma in WAT, SREBP1c in both liver and WAT, and GPAT in liver, and decreased the expression levels of PPARalpha, CPT1, and PDK4 in liver. These results give new insight into the different adaptive time course response to fasting in the expression of genes involved in lipid metabolism, thus pointing out the very rapid response of lipogenic genes, particularly in liver, and the later response of lipolytic genes, particularly in WAT.

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Epidemiological studies in humans and controlled intervention studies in animals have shown that nutritional programming in early periods of life is a phenomenon that affects metabolic and physiological functions throughout life. The phenotypes of health or disease are hence the result of the interaction between genetic and environmental factors, starting right from conception. In this sense, gestation and lactation are disclosed as critical periods. Continuous food restriction during these stages may lead to permanent adaptations with lasting effects on the metabolism of the offspring and may influence the propensity to develop different chronic diseases associated with obesity. However, the different outcomes of these adaptations on later health may depend on factors such as the type, duration, period, and severity of the exposure to energy restriction conditions, and they are, in part, gender specific. A better understanding of the factors and mechanisms involved in metabolic programming, and their effects, may contribute significantly to the prevention of obesity, which is considered to be one of the major health concerns of our time. Here, the different outcomes of maternal food restriction during gestation and lactation in the metabolic health of offspring, as well as potential mechanisms underlying these effects are reviewed.

Maternal prenatal undernutrition predisposes offspring to higher adiposity in adulthood. Mechanisms involved in these programming effects, apart from those described in central nervous system development, have not been established. Here we aimed to evaluate whether moderate caloric restriction during early pregnancy in rats affects white adipose tissue (WAT) sympathetic innervation in the offspring, and its relationship with adiposity development. For this purpose, inguinal and retroperitoneal WAT (iWAT and rpWAT, respectively) were analyzed in male and female offspring of control and 20% caloric-restricted (from 1–12 d of pregnancy) (CR) dams. Body weight (BW), the weight, DNA-content, morphological features and the immunoreactive tyrosine hydroxylase and Neuropeptide Y area (TH+ and NPY+ respectively, performed by immunohistochemistry) of both fat depots, were studied at 25 d and 6 m of age, the latter after 2 m exposure to high fat diet. At 6 m of life, CR males but not females, exhibited greater BW, and greater weight and total DNA-content in iWAT, without changes in adipocytes size, suggesting the development of hyperplasia in this depot. However, in rpWAT, CR males but not females, showed larger adipocyte diameter, with no changes in DNA-content, suggesting the development of hypertrophy. These parameters were not different between control and CR animals at the age of 25 d. In iWAT, both at 25 d and 6 m, CR males but not females, showed lower TH+ and NPY+, suggesting lower sympathetic innervation in CR males compared to control males. In rpWAT, at 6 m but not at 25 d, CR males but not females, showed lower TH+ and NPY+. Thus, the effects of caloric restriction during gestation on later adiposity and on the differences in the adult phenotype between internal and subcutaneous fat depots in the male offspring may be associated in part with specific alterations in sympathetic innervation, which may impact on WAT architecture.

We aimed to assess the lasting effects of caloric restriction in lactating rats on body weight and insulin sensitivity of their offspring. Dams were fed with either ad libitum standard diet or a 30% caloric restricted diet throughout lactation. After weaning, the offspring were fed with a normal-fat diet until the age of 15 wk, and then with a normal- or a high-fat (HF) diet until the age of 26 wk. Blood parameters were measured during ad libitum feeding conditions and after 14-h fasting. Food preferences were also measured. In dams, milk leptin concentration and leptin mRNA and protein levels in mammary gland were also determined. Caloric restricted dams showed higher mRNA and protein levels of leptin in mammary gland than controls, without significant changes in milk leptin concentration. The offspring of caloric restricted dams (CR) ate fewer calories and showed lower body weight gain and fat accumulation under the HF diet than their controls. CR also maintained unchanged circulating leptin levels under HF diet, whereas levels increased in controls. In addition, male CR were resistant to the increase of circulating triglycerides and of the homeostatic model assessment for insulin resistance produced in male controls under HF diet feeding; CR were also protected against the increased preference for fat-food occurring in females upon HF diet. These results suggest moderate caloric restriction during lactation protects from obesity development in offspring in adult life and from the related metabolic alterations, particularly dyslipidemia, insulin resistance, and hyperleptinemia, associated with HF diet feeding.

Hypothalamus is crucial in the control of energy intake and expenditure in mammals, presenting two interconnected populations of neurons producing orexigenic NPY/AgRP (neuropeptide Y; agouti related peptide) and anorexigenic POMC/CART (pro-opiomelanocortin; cocaine and amphetamine regulated transcript) neuropeptides. We aimed to shed more light on the response and sensitivity in the production of these neuropeptides to face nutritional changes, particularly food deprivation, and on the signals that regulate them. Male Wistar rats were fasted for 0, 4, 8 and 24h and refed for 3h after 8h fasting. mRNA levels of gastric and adipose tissue (retroperitoneal, mesenteric and inguinal) leptin, and of hypothalamic NPY, AgRP, POMC, CART, leptin receptor, SOCS3 (suppressor of cytokine signaling 3) and insulin receptor were analyzed. Gastric and circulating leptin, and circulating insulin, glucose and ghrelin were also determined. The only neuropeptide mRNAs that responded (increasing) to the short-term periods of fasting used were those of NPY (transiently) and AgRP, and these changes were accompanied by an increase in leptin receptor mRNA levels and by a decrease in adipose and gastric leptin expression and in the circulating levels of leptin, insulin and glucose, but without changes in circulating ghrelin. The elevation in AgRP and leptin receptor mRNA levels and the drop in circulating leptin were not reverted with refeeding. It is suggested that the induction of expression of the orexigenic molecules in NPY/AgRP neurons is an early event upon fasting, related with changes in leptin, insulin and glucose levels, but with the role of leptin signaling in particular.