Control of body weight:: a physiologic and transgenic perspective

In mammals, body weight is normally regulated around a set point by coordinated changes in food intake and energy expenditure. These changes are integrated under the influence of specific neural pathways and circulating signals. Almost 50 years ago it was first proposed that circulating signals generated in proportion to body fat stores influence appetite and energy expenditure in a coordinated manner to regulate body weight [1]. Of particular historical value are the classic parabiosis experiments which provided evidence that such circulating signals exist [2]. The positional cloning of the mouse ob gene and identification of its protein product, leptin, suggested that the long sought blood-borne lipostatic factor had been found [3]. Leptin appeared to fulfill the predictions of the lipostatic hypothesis in that it is mainly produced by adipocytes, circulates in proportion to total adipose tissue mass, and interacts specifically with a hypothalamic receptor to reduce food intake and promote weight loss [4, 5]. Paradoxically, almost one decade after the discovery of leptin it becomes clear that leptin alone does not explain all the outcomes of parabiotic studies. The evidence for the existence of additional adipostatic factors has already been reviewed [6, 7, 8]. With obesity as an increasingly important public health focus, a major development in the understanding of energy balance regulation has come with observations made in quite different biological spheres such as whole-body physiology and application of transgenic technology. Given that body weight regulation and food intake represent physiological processes that underpin both cell life and cell death, the presence of back-up mechanisms is not surprising. As with many biological systems, controversies and exceptions are not uncommon, especially to nascent pathways. Even in the age of molecular biotechnology there is a prominent role for physiological experimentation and reasoning in the discovery of important new regulatory and effector molecules. Great progress has been made in identifying several genes in spontaneous monogenic animal models of obesity as well as in understanding the molecular mechanisms underlying phenotypes of altered body weight, adiposity and fat distribution by creating transgenic animal models (see reviews [9, 10, 11]). Targeted expression and knockout of specific genes has been extremely helpful in establishing the physiological roles of certain genes in the control of energy metabolism in vivo. Transgenic approaches, however, also have limitations [9]. Overexpression or knockout of concrete genes, and the subsequent alterations in the expression of their encoded proteins at different steps of the regulatory pathway of adipogenesis, show the complexity and complementarity of genes involved in energy homeostasis. In this sense, the failure to produce an expected phenotype through transgenesis further reflects the existence of adaptive mechanisms to preserve crucial physiological functions. The analysis of a number of genetically obese mouse strains has clearly contributed to our understanding of body weight control. In particular, those strains that fail to synthesize either leptin or its functional receptor opened up the field to unravel the distinct metabolic abnormalities related to the development of an obese phenotype [3, 12, 13, 14]. Of interest, the outcome of spontaneous mutations, transgenesis or knockout of specific genes can be subdivided in animal models leading to obesity, mouse strains characterised by leanness and manipulations conferring resistance to obesity (Tables 1, 2, 3). Mutations affecting not only neurotransmitters, neuropeptides and their receptors but also transcription factors, transducers, hormones, cytokines, adhesion molecules as well as enzymes and transporters involved in glucose and lipid metabolism play a key role in the development of an obese phenotype.