Leptin
Evidence for an adipose tissue-derived homeostatic regulator of feed intake has accumulated for a number of years (Ahima and Flier, 2000; Ingvartsen and Andersen, 2000). These studies are built on the proposals by Kennedy (1953) stating that the amount of energy stored in adipose tissue mass represents a steady state between energy needs and energy derived from feed intake.
Since adipose tissue tends to be relatively stable for long periods in many mammals, he suggested that there must be a regulatory mechanism that effectively monitors changes in energy stores to elicit the needed change in feed intake to "restock" adipose reserves when demand is higher but to conversely reduce "deliveries" during periods of lower energy demand.This concept of a circulating fat-derived regulator of feeding behavior was bolstered by the discovery of genetic mutations in mice, obese (ob) and diabetes (db) phenotypes. Both of these recessive mutations lead to hyperphagia, decreased activity, and early onset of obesity. Parabiosis of wild type mice with ob∕ ob mice suppressed the weight gain in the defective mice but parabiosis of wild type mice with db/db mice caused marked hyperphagia and weight gain in the normal mice. This led to the idea that the ob gene locus was essential for the production of a circulating satiety factor and that the db locus encoded for a molecule capable of responding to this circulating agent. The product of the ob gene was subsequently named leptin (from the Greek word Ieptos, for "thin"), because of effects of the protein to reduce feed intake and body weight when injected into leptin-deprived or normal animals. Leptin satisfied many of the requirements of the adipose tissue regulator envisioned by Kennedy many years ago. Specifically, leptin is proposed to prevent obesity by reducing feed intake and increasing thermogenesis by affecting the hypothalamus.
These initial reports stimulated tremendous interest in leptin as an obesity preventive or weight-control agent in humans. However, like many aspects of homeostatic or homeorhetic regulation, simple answers are not often sufficient. Although leptin can provide a signaling pathway between adipose tissue and the central nervous system for monitoring of adipose tissue stores, the wide distribution of leptin receptors indicated that leptin affects many tissues and physiological systems.Leptin is a 16-kDa protein primarily produced in adipose cells, and in nonruminants circulates both in a free form and bound to other proteins in circulation. Energy stores influence expression of the leptin gene as shown by increased adipose tissue leptin mRNA and serum concentrations in obese mammals. There is also a positive correlation between body fat stores and leptin concentrations in blood, and secretion occurs with a circadian rhythm and may show episodic secretion. Although adipose tissue is the major source of leptin, relatively lower levels of expression are found in many other tissues. It may be that local tissue production of leptin is also important in addition to effects mediated by changes in circulating concentrations.
Cloning studies of the leptin receptor (Ob-R) indicate there are least six leptin receptor isoforms derived by alternative splice variants of the mRNA coding for the receptor. The receptor belongs to the family of cytokine receptors, which includes receptors for interleukins and Prl. Each of the leptin isoforms has identical extracellular ligand-binding domains, but they differ at the carboxy terminal end of the molecule or the cytoplasmic portion. Differences among the isoforms mean that there can be a great deal of variation in the signaling cascade stimulated by the binding of leptin to a particular receptor. Since expression of receptor isoforms is not uniform among target tissues, this adds an additional layer of complexity to understanding the physiological effects of leptin stimulation.
Unfortunately, studies in domestic animals and especially dairy animals are limited (Houseknecht et al., 1998). However, fasting increases the expression of the Ob-RL receptor in the sheep hypothalamus. Interestingly, leptin is also increased in the serum of animals fed high-energy diets, which may be related to decreased mammary development that can occur in these animals. Moreover, leptin appears in milk and is present in cultured bovine mammary epithelial cells. The cells also express mRNA for leptin and were impacted by additions of insulin and IGF-I, both of which are known mediators of mammary function. This suggests that leptin may be an autocrine or paracrine-signaling molecule in the mammary gland (Smith and Sheffield, 2002).
Leptin may also be involved in regulation of onset of puberty in heifers and ewes. It is well know that age of puberty, within limits, is affected by dietary energy intake, rate of growth, and accumulation of adipose tissue in the body. Given the role of leptin in adipose tissue metabolism, it is attractive to suggest that leptin is also important in this process. Short-term fasting of peripubertal heifers decreases leptin gene expression, circulating leptin, and LH (Williams et al., 2002). Leptin can modify activity of the hypothalamic- pituitary axis as well as the endocrine pancreas, depending on nutritional conditions, in cattle and sheep.
In conclusion, we have tried to provide an overview of major hormones and their sources, properties, and actions. We have also provided some examples of the details related to how target cells respond to hormones, growth factors, and similar regulators. These are clearly complex and difficult topics but it is important to slowly develop some appreciation of intricate interrelationships between these messengers and tissues. It is difficult overstate the relevance of the endocrine system in physiological regulation.