Oral Supplementation with Physiological Doses of Leptin During Lactation in Rats Improves Insulin Sensitivity and Affects Food Preferences Later in Life

Abstract

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.

Leptin intake during the suckling period improves the metabolic response of adipose tissue to a high-fat diet

“…However, in leptin-treated rats, a lower deposition of lipids in the liver together with a lower increase in the mRNA levels of PPARa and CPT1 may be indicative of a lower hepatic handling of fuel excess compared with their control counterparts. In this sense, we have previously described that leptin treatment protects the animals from diet-and age-related insulin resistance, 18,21 and the present results suggest that the prevention of dietinduced decrease of leptin receptor in adipose tissue may be associated with higher insulin sensitivity. Insulin resistance has also been related with visceral fat deposition, 22 and it is interesting to highlight that leptin-treated rats (with improved insulin sensitivity) show lower fat deposition in the mesenteric region under both feeding conditions, compared with control rats.…”

“…15,16 In this sense, we have previously shown in rats that the intake of moderate amounts of leptin during the suckling period prevents the development of overweight in later life, 18 and these long-term effects of leptin on body weight control were associated with an increased sensitivity to the central effects of leptin 21 and with a protection against central leptin resistance induced by dietary treatment. 18 Indirect evidence of the role of maternal milk-derived leptin in body weight control of infants has also been found in humans.…”

“…20 Furthermore, the oral administration of physiological doses of leptin during the suckling period prevents the high-fat (HF)-diet-induced adverse metabolic phenotype and improves insulin and central leptin sensitivity in adulthood. 18,21 These results suggested that leptin may be involved in early programming mechanisms of food intake and metabolism control systems. 16 These changes seen later in life can be summarized in higher sensitivity to leptin and a lower tendency to have diet-induced leptin resistance, which emphasizes the importance of the proper activity of leptin for body weight and metabolism management.…”

“…From day 1 to day 20 of lactation, and during the first 2 h of the beginning of the light cycle, 20 ml of the vehicle (water)F control groupFor a solution of recombinant murine leptin (PeproTech, London, UK) dissolved in waterFleptin-treated groupFwas given orally every day to the pups using a pipette, following the same protocol as described. 18,21 The amount of leptin given to animals was calculated as five times the average amount of the daily leptin intake from the mother's milk. 20 It was consider that this dose was within the 'physiological' range taking into account the great variation within mothers.…”

Evaluation of leptin in breast milk, lactating mothers and their infants

“…The results obtained in humans showing a negative association between BM leptin concentration and body weight gain in infants (Miralles et al, 2006), together with the direct cause-effect evidence obtained in rats (Picó et al, 2007; Leptin in breast milk, infants and mothers F Savino et al Sánchez et al, 2008), identify a new role for leptin as an essential element during lactation.…”