Effects of obesity and exercise on testicular leptin signal transduction and testosterone biosynthesis in male mice

Obesity, which has developed into a global epidemic, is a risk factor in most chronic diseases and some forms of malignancy. The discovery of leptin in 1994 has opened a new field in obesity research. Currently, we know that leptin is the primary signal from energy stores and exerts negative feedback effects on energy intake. However, most individuals with diet-induced obesity (DIO) develop leptin resistance, which is characterized by elevated circulating leptin levels and decreased leptin sensitivity. To date, though various mechanisms have been proposed to explain leptin resistance, the exact mechanisms of leptin resistance in obesity are poorly understood. Consequently, it's an important issue worth discussing regarding what the exact interrelations between leptin resistance and obesity are. Here, we review the latest advancements in the molecular mechanisms of leptin resistance and the exact interrelations between leptin resistance, obesity, and obesity-related diseases, in order to supply new ideas for the study of obesity. Copyright © 2014 Elsevier Inc. All rights reserved.

Leptin has key roles in the regulation of energy balance, body weight, metabolism, and endocrine function. Leptin levels are undetectable or very low in patients with lipodystrophy, hypothalamic amenorrhea, and congenital leptin deficiency (CLD) due to mutations in the leptin gene. For these patients, leptin replacement therapy with metreleptin (a recombinant leptin analog) has improved or normalized most of their phenotypes, including normalization of endocrine axes, decrease in insulin resistance, and improvement of lipid profile and hepatic steatosis. Remarkable weight loss has been observed in patients with CLD. Due to its effects, leptin therapy has also been evaluated in conditions where leptin levels are normal or high, such as common obesity, diabetes (types 1 and 2), and Rabson-Mendenhall syndrome. A better understanding of the physiological roles of leptin may lead to the development of leptin-based therapies for other prevalent disorders such as obesity-associated nonalcoholic fatty liver disease, depression and dementia.

Leptin is an adipocyte-derived hormone involved in a myriad of physiological process, including the control of energy balance and several neuroendocrine axes. Leptin-deficient mice and humans are obese, diabetic, and display a series of neuroendocrine and autonomic abnormalities. These individuals are infertile due to a lack of appropriate pubertal development and inadequate synthesis and secretion of gonadotropins and gonadal steroids. Leptin receptors are expressed in many organs and tissues, including those related to the control of reproductive physiology (e.g., the hypothalamus, pituitary gland, and gonads). In the last decade, it has become clear that leptin receptors located in the brain are major players in most leptin actions, including reproduction. Moreover, the recent development of molecular techniques for brain mapping and the use of genetically modified mouse models have generated crucial new findings for understanding leptin physiology and the metabolic influences on reproductive health. In the present review, we will highlight the new advances in the field, discuss the apparent contradictions, and underline the relevance of this complex physiological system to human health. We will focus our review on the hypothalamic circuitry and potential signaling pathways relevant to leptin’s effects in reproductive control, which have been identified with the use of cutting-edge technologies of molecular mapping and conditional knockouts.