LEAP-2 Counteracts Ghrelin-Induced Food Intake in a Nutrient, Growth Hormone and Age Independent Manner.

Data gleaned recently shows that ghrelin, a stomach derived peptide, and liver-expressed-antimicrobial peptide 2 (LEAP-2) play opposite roles on food intake. However, the data available with LEAP-2 in relation to in vivo studies are still very scanty and some key questions regarding the interplay among ghrelin and LEAP-2 remain to be answered. In this work, using rats and mice, we study fasting-induced food intake as well as testing the effect of diet exposure, e.g., standard diet and high fat diet, in terms of ghrelin-induced food intake. The anorexigenic effect of LEAP-2 on fasting induced food intake appears to be dependent on energy stores, being more evident in ob/ob than in wild type mice and also in animals exposed to high fat diet. On the other hand, LEAP-2 administration markedly inhibited ghrelin-induced food intake in lean, obese (ob/ob and DIO) mice, aged rats and GH-deficient dwarf rats. In contrast, the inhibitory effect on glucose levels can only be observed in some specific experimental models indicating that the mechanisms involved are likely to be quite different. Taken together from these data, LEAP-2 emerged as a potential candidate to be therapeutically useful in obesity.

Circulating LEAP-2 is associated with puberty in girls.

BACKGROUND/OBJECTIVES: Liver-expressed antimicrobial peptide 2 (LEAP-2) was recently identified as an endogenous non-competitive allosteric antagonist of the growth hormone secretagogue receptor 1a (GHSR1a). LEAP-2 blunts ghrelin-induced feeding and its plasma levels are modulated in response to nutritional status in humans. Despite the relevant role of ghrelin in childhood, puberty, and childhood obesity, the potential implication of LEAP-2 in these aspects remains totally unknown. We aimed to investigate the regulation of circulating plasma LEAP-2 in childhood and adolescent either lean or obese. METHODS AND RESULTS: Plasma levels of LEAP-2 were analyzed in a cross-sectional study with lean and obese children and adolescents (n = 150). Circulating LEAP-2 levels were significantly higher in girls than in boys independently of whether they were obese or lean. In addition, LEAP-2 was significantly increased (p < 0.001) in pubertal than in prepubertal girls, while no changes were found in boys between both developmental stages. Moreover, in girls LEAP-2 was positively correlated with insulin, IGF-1, HOMA-IR and triglycerides and negatively with ghrelin. In boys, LEAP-2 was positively correlated with leptin and negatively with vitamin D levels. CONCLUSION: This study reveals a sexual dimorphism in LEAP-2 levels in children and adolescents. These changes and the higher levels during puberty imply that LEAP-2 may contribute to some of the biological adaptations occurring during pubertal development in terms of food intake, energy balance, growth rate, and puberty onset. Future studies assessing LEAP-2 levels in longitudinal studies and its implications in growth rate, puberty onset, and reproductive hormones will help to understand the relevance of this hormone in this stage of life.

p107 Deficiency Increases Energy Expenditure by Inducing Brown-Fat Thermogenesis and Browning of White Adipose Tissue.

SCOPE: The tumor suppressor p107, a pocket protein member of the retinoblastoma susceptibility protein family, plays an important role in the cell cycle and cellular adipocyte differentiation. Nonetheless, the mechanism by which it influences whole body Energy homeostasis is unknown. METHODS AND RESULTS: The phenotype of p107 knockout (KO) mixed-background C57BL6/129 mice phenotype is studied by focusing on the involvement of white and brown adipose tissue (WAT and BAT) in energy metabolism. It is shown that p107 KO mice are leaner and have high-fat diet resistence. This phenomenon is explained by an increase of energy expenditure. The higher energy expenditure is caused by the activation of thermogenesis and may be mediated by both BAT and the browning of WAT. Consequently, it leads to the resistance of p107 KO mice to high-fat diet effects, prevention of liver steatosis, and improvement of the lipid profile and glucose homeostasis. CONCLUSION: These data allowed the unmasking of a mechanism by which a KO of p107 prevents diet-induced obesity by increasing energy expenditure via increased thermogenesis in BAT and browning of WAT, indicating the relevance of p107 as a modulator of metabolic activity of both brown and white adipocytes. Therefore, it can be targeted for the development of new therapies to ameliorate the metabolic syndrome.

Hypothalamic Mitochondrial Dysfunction as a Target in Obesity and Metabolic Disease.

Mitochondria are important organelles for the adaptation to energy demand that play a central role in bioenergetics metabolism. The mitochondrial architecture and mitochondrial machinery exhibits a high degree of adaptation in relation to nutrient availability. On the other hand, its disruption markedly affects energy homeostasis. The brain, more specifically the hypothalamus, is the main hub that controls energy homeostasis. Nevertheless, until now, almost all studies in relation to mitochondrial dysfunction and energy metabolism have focused in peripheral tissues like brown adipose tissue, muscle, and pancreas. In this review, we highlight the relevance of the hypothalamus and the influence on mitochondrial machinery in its function as well as its consequences in terms of alterations in both energy and metabolic homeostasis.