Feed intake is the cornerstone of animal productivity. The consequences of inadequate intake include reduced growth, delayed puberty, infertility, reduced milk production, and lowered resistance to parasites and disease. Conditions also exist where intake is fully adequate for good health and well-being, but is limiting for optimum performance and productivity. Factors that influence intake include age, metabolic demand (gestation, lactation, level of physical activity), thermal environment, disease, and psychosocial stress. An understanding of the interactions between these factors and the mechanisms of appetite control is fundamental to the development of practical approaches to optimize feed intake and associated productivity.
The involvement of the brain in the control of food intake has long been recognized. Classic lesioning studies with rats identified the hypothalamus as the site of important appetite-regulating pathways. Lesions of the ventromedial hypothalamus produced uncontrollable hunger and obesity. Conversely, lesions of the lateral hypothalamus removed the drive to eat. The concept of two primary brain centers for appetite control provided an important conceptual framework for early studies. We now know, however, that this early model is a great oversimplification of the complex mechanisms and pathways involved in the neural control of appetite. A variety of appetite-stimulating and -suppressing hormones and neurotransmitters are produced in the CNS and periphery. These compounds bind and activate their CNS receptors, triggering downstream pathways/regulators that result in appropriate changes in ingestive behavior. A few of the appetite-stimulating neurohormones of recent interest include neuropeptide Y (NPY), the orexins, melanin-concentrating hormone (MCH), endorphins, galanin, GHRH, (-amino butyric acid (GABA), and agouti-related protein (AGRP). Negative regulators of appetite include leptin, bombesin, glucacon-like peptide-1 (GLP-1), CRH, urocortin, cholecystokinin (CCK), cocaine and amphetamine-regulated transcript (CART), and "-MSH. The effects of urocortin (a CRH-related peptide) on feed intake and neuroendocrine function in gilts will be the subject of a subsequent paper in this symposium. The discovery of leptin in 1995 was particularly significant event in terms of 1) identifying a major missing link involved in the signaling of energy status from the periphery to the brain and 2) stimulating a renewed research interest in the identification and manipulation of central targets for appetite regulation. Recent significant advances in leptin-related research in domestic animals will be the focus several research papers and an invited presentation later in this symposium.
While the importance of feed intake in livestock is unquestioned, studies on appetite control in domestic species are relatively few compared to those in laboratory rodents. World-wide interest in appetite control, coupled with the advent of new research technologies and approaches has prompted new appetite-related research in a growing number of domestic animal laboratories.
Most current research approaches in livestock appetite control begin with the elucidation of cDNA or gDNA sequences for appetite regulators. The availability of cDNA clones provides information on amino acid sequences, which then may be synthesized (peptides) or recombinantly expressed (protein hormones, receptors). The cDNA clones and sequence data for livestock orexin and leptin have resulted in the production of hormones that have been successfully used for studies in sheep and swine. Recombinant leptin is also being used for the development of new antibodies and immunoassays for cattle, sheep, swine, and poultry. Site-directed mutagenesis can be applied to cDNA clones for the structure-function analyses needed for the development of new agonists and antagonists. A leptin analog (LY355101) will be discussed in a research presentation later in this symposium. The production of cDNA clones and sequence data for livestock appetite-regulators provides primers and probes that contribute to international gene mapping programs and to the identification of polymorphisms for marker-assisted selection.
The determination of tissues where appetite-regulators and/or their hormones are produced is an important first step in determining mechanisms of action for newly-discovered compounds. Leptin is a classic example, where this hormone is produced in adipose tissue, but interacts with receptors in the brain to inhibit feed intake. Similarly, CART mRNA has been found in peripheral tissues, as well as in the CNS. Evidence of CART production outside of the CNS has prompted studies entailing peripheral administration, where initial evidence has shown rapid entry of CART into the brain. Our work with the pig has shown a variety of tissue distribution patterns for different appetite-regulators. In the tissues we have screened, we have found MCH mRNA only in the hypothalamus. In contrast, mahogany mRNA has been detectable in every tissue we have screened. A more typical example of mRNA tissue distribution is the mRNA for type 2 orexin receptor (ORX2R). ORX2R mRNA is readily detected in hypothalamus, pituitary and adrenal, yet low levels of expression are also seen in fat, muscle, thymus, spleen, and testis. The presence of ORX2R mRNA in pituitary has prompted research on possible direct actions of orexin on pituitary hormone secretion and production.
Having established the tools needed to monitor appetite-regulating gene expression, the next great challenge will be to elucidate the physiological roles of these compounds on feed intake and productivity in our domestic species. Based on our knowledge of factors that affect feed intake, the expression of CNS feed intake regulators should be altered by nutritional status, genetics, thermal stress, psychological stress, physiological/ environmental conditions that affect energy expenditure, and disease. Integration of appetite-control research into existing models of suppressed intake is needed. An excellent example is the disease-challenged animal, which will be discussed in an invited presentation and a research paper in this symposium. Additionally, partnerships with animal nutrition laboratories will be extremely valuable in moving this field of research forward. Studies of known appetite-regulators will provide valuable information on the physiology of appetite control in domestic animals. Cloned livestock cDNAs for many hypothalamic appetite regulators and their receptors have recently been produced and have formed the basis for studies of appetite-related gene expression in swine, cattle, sheep, and poultry. Ongoing studies in our laboratory are generating some of the first physiological data on the regulation of porcine orexin, orexin receptor, NPY, AGRP, MC4-R, leptin, leptin receptor, and MCH gene expression.
New physiological data will establish model conditions that will reliably provide high contrasts between animals in the expression of appetite regulators. Transcript profiling studies, using cDNAs from such animals, have been initiated. These studies offer an exciting potential for new advances in our understanding of feed intake control. New roles for known genes may be identified, as well as the detection of as-yet unknown gene products. The analysis of reading frames of novel sequences may well reveal additional neurohormones and new central targets for appetite regulation.