Physiological Models of Leptin Resistance

In common forms of obesity, animals and humans become leptin resistant associated with impaired regulation of energy homeostasis. Over the last decade, significant advances in delineating the underlying mechanisms have been achieved. As well as the obvious scientific progress obtained by novel transgenic animals, natural and physiological models of leptin resistance such as the Siberian hamster (Phodoups sungorus), the field vole (Microtus agrestis) or the rat during pregnancy have also provided invaluable insight into the dynamic long-term control of energy homeostasis. Seasonal (in the hamster) and pregnancy-induced leptin resistance are characterised by a modulation of the leptin signalling cascade downstream of its receptor in the hypothalamus. In this state, leptin-induced phosphorylation of the important transcription factor, signal transducer and activator of transcription 3 (STAT3), is impaired in the arcuate nucleus and the ventromedial hypothalamus (only during pregnancy). This is accompanied by elevated levels of leptin signalling inhibitors such as the suppressor of cytokine signalling (SOCS3) and the protein tyrosine phosphatase 1B (PTP1B). The janus kinase 2 (JAK2)-STAT3 signalling pathway might be modulated by a dual function of the tyrosine residue Tyr985 in the intracellular domain of the leptin receptor. In seasonal animals, SOCS3, most importantly seems to act as a 'molecular switch' enabling a photoperiod-induced alteration in leptin signalling and subsequent adjustments in energy homeostasis to allow attainment of a new body weight set-point. These physiological models show that animals can exhibit leptin resistance as an adaptive response to meet new physiological or environmental challenges, promoting the survival of the species during times of increased metabolic demand. The molecular mechanisms mediating physiological and/or pathological leptin resistance, like during diet induced obesity, might be very similar involving hypothalamic SOCS3. Investigation of these models might further provide new insight into the dynamic complexity of energy homeostasis.