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A Physiological Role of Breast Milk Leptin in Body Weight Control in Developing Infants

Objective: Leptin, a hormone that regulates food intake and energy metabolism, is present in breast milk. The aim of this study was to determine whether milk leptin concentration is correlated with maternal circulating leptin and BMI and with body weight gain of infants.

Secretory granules of endocrine and chief cells of human stomach mucosa contain leptin.

BACKGROUND: Leptin plays an important role in the control of food intake and body weight homeostasis. In humans, leptin is produced by adipocytes, placental cells and secretory cells of the mammary epithelium. Recently, it has been reported that stomach glands produce leptin in rats.OBJECTIVE: To test the expression of leptin protein in human stomach and localize, by immunocytochemistry, the specific cell type producing leptin.DESIGN: Endoscopic stomach biopsies of six patients were used to investigate leptin production in the fundic epithelium using reverse transcription polymerase chain reaction (RT-PCR) of RNA. Leptin protein was detected by immunoblot analysis and localized by immunohistochemistry and ultrastructural immunocytochemistry (immunogold method).RESULTS: Human gastric epithelium expresses leptin mRNA and leptin protein. The cells in the lower half of the stomach glands were immunoreactive for leptin. Ultrastructural immunocytochemistry showed leptin immunoreactivity in the pepsinogen granules of chief cells, but the granules of a specific endocrine cell type in the basal portion of the glands were also positive.CONCLUSIONS: Our results suggest that gastric leptin could function in the short-term system to control feeding behaviour and is probably secreted in the stomach lumen by chief cells and into the stomach circulation by a special type of endocrine cell.

The intake of physiological doses of leptin during lactation in rats prevents obesity in later life

Background:There is epidemiological evidence that perinatal nutritional factors may have long-term effects on obesity. Which nutrients or food components are involved in this programming mechanism are unknown. Breast milk contains leptin, a hormone that regulates food intake and energy expenditure, and previous studies in rats have shown that leptin orally administered during lactation exerts anorexigenic effects.Objective:To evaluate whether supplementation with physiological doses of oral leptin during lactation has long-term effects on body weight regulation.Design:A daily oral dose of leptin (equivalent to five times the amount of leptin ingested normally from maternal milk during the suckling period) or the vehicle was given to suckling male rats during lactation. Animals were fed after weaning with a normal fat (NF) or a high-fat (HF) diet. We followed body weight and food intake of animals until the age of 6 months, and measured the size of adipose tissue depots, the thermogenic capacity, the expression of leptin in the stomach and adipose tissues and the expression of two appetite-related peptides (neuropeptide Y (NPY) and proopiomelanocortin (POMC)), leptin receptor (OB-Rb) and suppressor of cytokine signalling 3 (SOCS-3) in the hypothalamus at the age of 6 months.Results:Leptin-treated animals had, in adulthood, lower body weight and fat content and ate fewer calories than their untreated controls. Unlike adipocitary leptin production, adult animals that were leptin-treated during lactation displayed higher gastric leptin production without changes in OB-Rb mRNA levels. In addition, in response to HF diet, leptin-treated animals (contrary to controls) showed lower hypothalamic NPY/POMC mRNA ratio. Hypothalamic OB-Rb mRNA levels decreased in control animals as an effect of HF diet feeding, but remained unchanged in leptin-treated animals; SOCS-3 mRNA levels were lower in leptin-treated animals than in their controls, both under normal or HF diet.Conclusion:The animals that received leptin during lactation become more protected against fat accumulation in adult life and seem to be more sensitive to the short- and long-term regulation of food intake by leptin. Thus, leptin plays an important role in the earlier stages of neonatal life, as a component of breast milk, in the prevention of later obesity.

THE UNCOUPLING PROTEIN, THERMOGENIN

The uncoupling protein (UCP) or thermogenin is a 33 kDa inner-membrane mitochondrial protein exclusive to brown adipocytes in mammals that functions as a proton transporter, allowing the dissipation as heat of the proton gradient generated by the respiratory chain and thereby uncoupling oxidative phosphorylation. Thermogenesis (heat production) in brown adipose tissue, which is activated in response to cold exposure or chronic overeating, depends largely on UCP activity. Norepinephrine, released from sympathetic terminals and acting via beta-adrenoceptors and cAMP, is the main positive regulator of both UCP synthesis and activity. Brown fat thermogenesis plays a critical role in thermoregulation and in overall energy balance, at least in rodents. Manipulation of thermogenesis, whether through UCP or through analogous uncoupling proteins, could be an effective strategy against obesity.

Sex-differential Expression of Metabolism-related Genes in Response to a High-fat Diet

Objective: The aim of this work was to determine the sex‐associated differences in the expression of genes related to lipid metabolism and fuel partitioning in response to a high‐fat (HF) diet in rats, and whether this is linked to the higher tendency of males to suffer from metabolic disorders.

Leptin intake during lactation prevents obesity and affects food intake and food preferences in later life

Breast milk is practically the only food ingested during the first months of life in fully breastfed infants and it is assumed to match the infants nutritional needs. Epidemiological data suggest that breastfeeding compared with infant formula feeding confers protection against several chronic diseases later on in life and, particularly, against obesity and related medical complications. However, causality has not been related to any specific compound of breast milk. Recent data in our laboratory have identified leptin as the specific compound that is responsible for some of these beneficial effects of breastfeeding. The hormone leptin was identified as a key candidate because it is present in breast milk, but is not present in infant formula, and when ingested during the suckling period can be absorbed by the immature stomach exerting biological effects. Evidence of the beneficial effects of breast milk leptin was obtained from human studies, showing that milk-borne maternal leptin appeared to give moderate protection to infants from excess weight gain. Direct cause-effect evidence was obtained in rats, where oral leptin supplementation during the suckling period resulted in a decrease in food intake, affected food preferences in favour of carbohydrates versus fat, and protected against overweight in adulthood, with an improvement of related parameters such as leptin and insulin sensitivity. These findings open a new area of research on the use of leptin in the design of more appropriate infant formula, which is significant considering the increasing incidence of obesity and its associated medical complications.

Moderate caloric restriction during gestation results in lower arcuate nucleus NPY- and αMSH-neurons and impairs hypothalamic response to fed/fasting conditions in weaned rats

Aim: We aimed to characterize the developmental programming effects of moderate caloric restriction during early pregnancy on factors involved in hypothalamic control of energy balance.

Moderate Caloric Restriction during Gestation in Rats Alters Adipose Tissue Sympathetic Innervation and Later Adiposity in Offspring

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.

Response to carbohydrate and fat refeeding in the expression of genes involved in nutrient partitioning and metabolism: striking effects on fibroblast growth factor-21 induction.

This study aimed to assess the effects of carbohydrate (CHO) and fat intake on the expression of key genes related with nutrient partitioning and metabolism in main tissues involved in energy metabolism (white adipose tissue, liver, and skeletal muscle). Rats were studied under different conditions: feeding state, 24 h fasting, and 12 h refeeding after 24 h fasting with isocaloric amounts of CHO or fat. Fat, but not CHO, refeeding was associated with an increase in serum and liver triglyceride content. Main changes in gene expression elicited by CHO compared with fat refeeding were: 1) higher expression levels of genes related with lipogenesis (PPARgamma2, ChREBP, FAS), glucose uptake and metabolism (GLUT4, HKII), fatty acid uptake (LPL, CD36), and lipolysis (ATGL, HSL) in white adipose tissue; 2) higher expression levels of genes related with lipogenesis (FAS, SCD1) but lower ones related with fatty acid uptake (CD36) and oxidation (PPARalpha, CPT1, PDK4) in liver; and 3) higher expression levels of GLUT4 but lower ones related with fatty acid oxidation (PDK4 and UCP3) in muscle. It is worth mentioning that both CHO and fat refeeding resulted in a robust increase in both hepatic mRNA and circulating levels of fibroblast growth factor-21, compared with fasted levels. In summary, these results, showing marked differences in gene expression after CHO and fat refeeding, can explain diet-associated differences in fuel handling and partitioning between tissues; in addition, a role of fibroblast growth factor-21 in metabolic adaptations, not only in the ketotic state but also to face an unbalanced nutritional situation, is suggested.

Gastric leptin: a putative role in the short-term regulation of food intake

The discovery of the production of leptin by the stomach, in addition to its production by adipose tissue, has initiated new investigation into the possible role of this protein in the digestive physiology, in particular in the short-term control of energy balance. Leptin has been identified in the lower half of the stomach glands both in the pepsinogen granules of chief cells and in the granules of a specific endocrine cell type, suggesting that leptin action is exerted by both exocrine and endocrine pathways. Gastric leptin is sensitive to the nutritional state, being rapidly mobilized in response to food intake following fasting, or after the administration of satiety factors; this suggests a role for this protein in the short-term regulation of feeding, acting in collaboration with satiety peptides such as cholecystokinin. Leptin, produced by gastric cells and by adipocytes, could act on both acute and chronic regulation of feeding behaviour respectively, giving information to the brain on the availability of external (food) and internal (fat depots) energy resources, thus participating in short- and long-term satiation.