Review Hypothalamic neuropeptide mechanisms for regulating energy balance: from rodent models to human obesity Julian G. Mercer a, * , John R. Speakman a,b a Rowett Research Institute, Aberdeen Centre for Energy Regulation and Obesity ACERO), Bucksburn, Aberdeen AB21 9SB, UK b Department of Zoology, University of Aberdeen, Aberdeen AB24 2TZ, UK Received 20 October 2000; accepted 1 December 2000 Abstract In small rodents there is compelling evidence of a lipostatic system of body mass regulation in which peripheral signals of energy storage are decoded in the hypothalamus. The ability of small mammals to defend an appropriate mass against imposed energy imbalance has implicated hypothalamic neuroendocrine systems in body mass regulation. The effect of the neuropeptide systems involved in this regulation is primarily compensatory. However, small mammals can also effect changes in the level of body mass that they will defend, as exempli®ed by seasonal species. Regulatory control over fat mass may be relatively loose in humans; the sizes of long-term storage depots may not themselves be regulated, but rather may be a consequence of temporal variations in the matching of supply and demand. Whether food intake is regulated to match energy demand, or to match demand and to regulate storage, it is clear that physiological defects or genetic variation in hypothalamic and peripheral feedback systems will have profound implications for fat storage. Study of mechanisms implicated in energy homeostasis in laboratory rodents is likely to continue to identify targets for pharmacological manipulation in the management of human obesity. q 2001 Elsevier Science Ltd. All rights reserved. Keywords: Body mass; Body weight; Body weight set point; Siberian hamster; Phodopus; Photoperiod; Hypothalamic neuropeptides; Leptin; Melanocortin Contents 1. Introduction ............................................................................ 101 2. An evolutionary perspective on the need to regulate fat storage in small mammals ........................ 102 3. Hypothalamic involvement in body mass regulation ............................................... 103 4. Hypothalamic neuropeptides in body mass defence ............................................... 104 5. Programmed body mass change in mammals .................................................... 106 6. Body massÐthe sliding `set point' ........................................................... 107 7. Dietary manipulation of defended body mass .................................................... 107 8. Seasonal body mass regulation in the Siberian hamster ............................................. 108 9. An evolutionary perspective on fat storage regulation in humans ...................................... 110 10. The human hypothalamus in control of food intake and adiposity ..................................... 111 11. Conclusions ............................................................................ 112 Acknowledgements .......................................................................... 113 References ................................................................................ 113 1. Introduction All animals eat food to satisfy their needs for energy and nutrients. These requirements are not in a ®xed ratio because needs vary according to what the individual is doing at any particular time, i.e. growing, reproducing, migrating etc. Moreover the problem of meeting these demands is exacer- bated by the fact that food is extremely heterogeneous in its composition. The task is therefore to pick from the available foods a suitable combination of food types and quantities to satisfy diverse and temporally variable requirements. Due to alternative behavioural necessities, food intake must be Neuroscience and Biobehavioral Reviews 25 2001) 101±116 PERGAMON NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS 0149-7634/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved. PII: S0149-763400)00053-1 www.elsevier.com/locate/neubiorev * Corresponding author. Tel.: 144-1224-716662; fax: 144-1224- 716653. E-mail address: jgm@rri.sari.ac.uk J.G. Mercer).