Leptin Receptors

Elizabeth C. Cottrell and Julian G. Mercer


1 Introduction 4

2 Historical Perspectives on the Discovery of Leptin 5

3 Homeostatic Regulation of Feeding in the Central Nervous System 6

4 Regulation of Leptin Production and Receptor Levels 8

5 Leptin Receptor Signalling 9

6 Obesity and Leptin Resistance 11

7 Leptin Signalling and Reward Pathways in the Control of Feeding 13

8 Pharmacological Modification of Leptin Signalling 14

9 Conclusions and Future Directions 16

References 16

Abstract The hormone leptin, secreted predominantly from adipose tissue, plays a crucial role in the regulation of numerous neuroendocrine functions, from energy homeostasis to reproduction. Genetic deficiency as a consequence of leptin or leptin receptor mutations, although rare in humans, leads to early onset of chronic hyperphagia and massive obesity. In most human obesity, however, leptin levels are chronically elevated. Under these conditions of persistent hyperleptinaemia, and particularly when obesity is associated with a high-fat diet, leptin resistance develops, and signalling through the leptin receptor is curtailed, fuelling further weight gain. Here, we review the role of leptin receptors in the regulation of feeding and obesity development. Leptin receptors are found in each of the major components of the CNS "feeding" circuitry—the brainstem, hypothalamus and

Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, Scotland EH16 4TH, UK

J.G. Mercer

Division of Obesity and Metabolic Health, Rowett Institute of Nutrition and Health, University of Aberdeen, Bucksburn, Aberdeen, Scotland AB21 9SB, UK

H.-G. Joost (ed.), Appetite Control, Handbook of Experimental Pharmacology 209, 3

DOI 10.1007/978-3-642-24716-3_1, © Springer-Verlag Berlin Heidelberg 2012

distributed reward centres. Through these receptors, leptin exerts influences on signalling and integration within these circuits to alter feeding behaviours. Although some progress is now being made with peptide analogues, the leptin receptor has not proved to be amenable to small molecule pharmacological intervention to date. Where clinical benefit from recombinant leptin administration has been achieved, this has been under circumstances of complete endogenous leptin deficiency or relative hypoleptinaemia such as in lipodystrophy.

Keywords Leptin • Leptin receptors • Obesity



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