After the discovery of leptin, the initial hypothesis that human obesity results from a deficiency in leptin has failed. Obese humans have high plasma leptin concentrations related to the size of adipose tissue, but this elevated leptin signal does not induce the expected response. This fact suggests that obese humans are resistant to the effects of endogenous leptin. The resistance is also shown by the lack of effect of exogenous administration to induce weight loss in obese patients . Leptin resistance may be defined as reduced sensitivity or complete insensitivity to leptin action, as occurs for insulin in type 2 diabetes .
Human and rodent studies indicate that the major cause of this resistance arises from an inability of leptin to cross the blood-brain barrier . The leptin transporter is a saturable system: beyond a certain plasma leptin level, increased production by the growing fat mass would be futile. Furthermore, severe hyperleptinaemia might down-regulate the leptin transporters and make the situation worse . This mechanism may explain why the exogenous administration of leptin to treat obesity might be ineffective if endogenous leptin has already saturated its transporters. However, the blood-brain barrier resistance is acquired and to some extent it is reversible with weight loss . In rodents, it is well known that the down-regulation of leptin signalling receptor is one of the mechanisms by which the effects of leptin are lost . The hypothalamic leptin receptor signalling is not down-regulated in obese patients. Probably, for the presence of the blood-brain barrier saturable system, the hypothalamic interstitial leptin concentration may only be mildly elevated, at least compared with the lep-tin serum concentration .
It is also possible that resistance is determined by chronic elevation of hypothalamic leptin tone, as studied in rats, or by suppressing intracellular signalling [42, 57]. The presence of negative regulators of leptin signalling such as SH2-containing protein tyrosine phosphatase-2 (SHP-2) and protein tyrosine phosphatase-lB (PTP-1B) has been observed in diet-induced obese animals. It has been found that deficiency of the suppressor of cytokine signalling-3 (SOCS-3) is associated with increased leptin sensitivity in the brain and has conferred resistance to diet-induced obesity in animals . This widespread occurrence of lep-tin resistance could reflect the fact that the inability to store energy efficiently at times of abundance is evolutionarily disadvantageous . Leptin may therefore play an important role during periods of starvation, but may be less significant when food is freely available .
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