Leptin-induced weight loss is not solely mediated by anorexia

The discovery of the ob-gene product leptin in 1994(1–2) and the subsequent identification of grosslyobese children lacking leptin (3) or its receptor (4) con-siderably increased the expectation of finding an effec-tive cure for grossly obese humans. Very soon after itsdiscovery it became evident, however, that a deficiencyof leptin did not account for obesity in the largemajority of patients and the treatment of obese subjectswith recombinant leptin was rather disappointing (5).One of the most important reasons for the lack of effi-ciency of leptin to regulate energy balance in the cen-tral nervous system (CNS) of humans is the saturabletransport mechanism allowing for (or rather impeding)the penetrance of leptin into the CNS (6, 7). Alternativesystems involved in the regulation of weight regulationhave therefore been sought, such as leptin down-stream peptides (8) or mechanisms confined to theregulation of peripheral weight and its metabolic impli-cations (9).In the last few years, one major focus of leptin researchhas shifted from central regulation of appetite andenergy expenditure to the peripheral actions. Consistentwith the cytokine structure of its receptors, the action ofleptin has been linked to the proliferation of various tis-sues leading to effects such as wound healing (10).However, there is increasing new evidence revivingthe role of leptin in weight regulation. It has recentlybeen demonstrated that patients with lipodystrophyhave significantly reduced plasma leptin concen-trations. Lipodystrophy consists of a heterogeneousgroup of rare disorders characterized by partial or gen-eralized loss of adipose tissue. The application of leptinreduces hepatic fat mass and improves insulin sensi-tivity in humans suffering from this condition (11–13).Direct evidence that leptin directly reduces hepaticlipid synthesis independent of its effect on appetite con-trol now comes from Friedman’s group (14). Usingtranscription profiling they identified the gene mostspecifically repressed in the liver of leptin-treatedob/ob (i.e. leptin-deficient) mice. It encodes for the stear-oyl-CoA desaturase-1 (SCD-1). This iron-containingenzyme catalyses a rate-limiting step in the synthesisof hepatic fatty acids. The principal product of SCD-1is oleic acid which is formed by desaturation of stearicacid. Therefore SCD-1 is a key enzyme leading to anincrease in energy storage (15).Cohen and co-workers (14) showed that in theleptin-deficient ob/ob mouse leptin treatment comple-tely normalized the elevated SCD-1 gene expressionand enzymatic activity. Levels of hepatic monosaturatedfatty acids, the products of SCD-1 that were elevated inthe leptin-deficient mice, normalized by 12 days ofleptin treatment.In order to distinguish between SCD-1 and non-SCD-1leptin actions, ob/ob mice were compared with doublemutant leptin-deficient ob/ob and SCD-1-deficientab