Modulation of susceptibility to weight gain and insulin resistance in low birthweight rats by treatment of their mothers with leptin during pregnancy and lactation

Abstract

OBJECTIVES:To investigate whether administration of leptin to rats during pregnancy and lactation affects placental 11b-hydroxysteroid dehydrogenase (11b-HSD2) activity and the susceptibility of their offspring to weight gain and insulin resistance. DESIGN: Pregnant rats fed on a low-protein diet were administered leptin or saline by subcutaneous minipump from day 14 of gestation and throughout lactation. A further group was fed a normal diet and given saline. After weaning, the offspring of each group were fed on a normal diet until 6 weeks of age and then half of each group was transferred to a high-fat diet until 12 months of age. RESULTS: Plasma leptin levels were raised two-fold on days 16-18 of pregnancy in the leptin-treated dams, but, despite a constant rate of infusion, at parturition they dipped to control levels before rising again. The activity of placental 11b-HSD2 was reduced by the low-protein diet; this reduction was prevented by treating the dams with leptin. The male offspring of the salinetreated dams gained more weight and had higher plasma leptin levels on the high fat than the chow diet, but the offspring of the leptin-treated dams did not. Fasting blood glucose and intraperitoneal glucose tolerance at 6 and 12 months of age was unaffected by the high-fat diet, but only the offspring of the leptin-treated dams achieved this control without raised insulin levels. CONCLUSIONS: The rate of leptin clearance appears to increase at parturition. The administration of leptin to rats during late pregnancy and lactation makes their male offspring less susceptible to high-fat-diet-induced weight gain and insulin resistance.

Developmental and epigenetic pathways to obesity: an evolutionary-developmental perspective

“…54,55 This in turn is associated with reversal of the changes in metabolic gene expression and methylation of these genes in liver tissue when examined as adults. 20 There are gender differences, 55,56 either reflecting the different role of body mass in reproductive success across the genders or different timings of maturation between species.…”

Thrifty energy metabolism in catch-up growth trajectories to insulin and leptin resistance

“…18,19 The clinical relevance of these observations, like the ontogeny of early-life leptin levels in humans, has yet to be established, particularly in the context that leptin is present in breast milk 20 but not in infant formulae, and that breast-feeding has been found to lower the risk for obesity compared with formula feeding. 21,22 Nonetheless, the findings that low leptin levels in cord blood closely reflect low adipose mass at birth, and strongly predict high rates of weight gain during infancy 23 , are consistent with a role for major perturbations in leptin production in developmental programming.…”

Programming of obesity and cardiovascular disease

“…Even after giving high-fat high-sucrose 'cafeteria' diet, the low protein progeny does not appear to become more obese than rats that were fed normally in utero. 38,40 In mice however, offspring of dams fed a low protein diet during pregnancy and caught up during lactation by nursing by control dams gained more weight when given free access to a cafeteria diet. 41 Our recent results (unpublished data) underline the importance of an early catch-up growth after intrauterine nutrient shortage, since in these conditions, rats develop a higher obesity rate than controls, both after protein or calorie restriction, whereas they do not in the absence of rapid catch-up growth.…”