New insights into leptin resistance by modifying cytokine receptor signal transduction

doi:10.1530/eje.1.01859

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New insights into leptin resistance by modifying cytokine receptor signal transduction

Jörg Dötsch, Wolfgang Rascher and Udo Meißner

Klinik für Kinder und Jugendliche, Universität Erlangen-Nürnberg, Germany

(Correspondence should be addressed to J Dötsch, Department of Paediatrics, Friedrich-Alexander-University Erlangen, Loschgestrasse 15, 91 054 Erlangen, Germany; Email: Joerg.Doetsch{at}kinder.imed.uni-erlangen.de)

It has been widely accepted that leptin treatment of obese humansis restricted to those few subjects that suffer from congenitalleptin deficiency (1). The peripheral administration of leptinto overweight patients with fat mass-adjusted normal serum leptinconcentrations does not reduce body weight substantially (2).These observations suggest that leptin resistance in obese humanbeings is similar to insulin resistance in patients with type2 diabetes mellitus.

Several mechanisms contributing to leptin resistance have beenidentified so far. First, a saturable transporter allowing leptinto pass the blood–brain barrier was discovered. This mechanismimpedes the hormone’s transfer to the hypothalamus oncecertain plasma concentrations are exceeded (3, 4). Secondly,negative regulators of leptin signalling such as the tyrosinephosphatases protein tyrosine phosphatase 1B and SH-containingprotein tyrosine phosphatase (5–8) as well as the suppressorsof cytokine signalling (Socs) (9) have been shown to contributeto leptin resistance. Since leptin indeed acts via a cytokinereceptor, the latter group is of particular interest. Socs moleculesinhibit the function of cytokines and of other proteins suchas leptin by interfering with receptor-dependent JAKs or STATs(Fig. 1). In fact, peripheral leptin administration in micehas previously been shown to increase the hypothalamic concentrationof Socs3 (10). This would suggest that increased serum concentrationsof leptin in obese subjects might impede leptin function byinterfering with receptor signalling through Socs proteins.At first glance it appears to be simple to test this hypothesisby watching the effect of leptin in a Socs3-deficient knock-outmouse model. However, homozygous Socs3 knock-out mice are stillborndue to placental defects (11).

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Figure 1 Mechanisms of hypothalamic leptin action, leptin signal transduction and key players in leptin resistance with regard to obesity control.

Therefore, it is of great interest that two recent articleseventually shed light on the role of Socs3, the suppressor ofleptin function, using two different approaches. In the firstreport J S Flier’s group used a heterozygous Socs3 +/–mouse model to demonstrate in this non-lethal animal model reducedSocs3 mRNA expression in the hypothalami (12). The second reportused a Cre-loxP system to allow neural cell-specific specificSocs3 knock-out not interfering with the non-neuronal functionsof the protein (13). They were able to demonstrate completeabsence of Socs3 in the brain of their animals.

Using these two different approaches the two papers achieveamazingly consistent findings: (i) Socs3 +/–-animals aswell as neural cell-specific knock-out mice do not gain significantlymore weight or increase food intake compared with their normallyfed littermates even when offered a high-fat diet. In contrast,wild-type mice developed a significant increase in food intakeand body weight. This suggests that leptin-induced suppressionof appetite is enhanced in the Socs3-deficient animals and thatSocs3 is a mediator of leptin resistance. (ii) While wild-typemice develop insulin resistance when exposed to high-fat dietthis is not the case in the two different knock-out animalswith reduction or absence of Socs3 in the brain. This couldbe demonstrated by normalisation of insulin secretion as wellas a normalised response to glucose tolerance tests. (iii) Withregard to the mechanism of action, in both studies the hypothalamicresponse to peripheral leptin administration was increased inthe knock-out animals, suggesting a lesser degree of impairmentof leptin receptor function. Specifically, STAT3 phosphorylation,being the most important mode of signal transduction of leptin,was increased in both the heterozygous Socs3 and the neuralcell-specific Socs3 knock-out following leptin application.

However, while the principal messages of both communicationson Socs3 suppression are in line, some of the findings are distinct:Howard et al. (12) do not report alterations in the hypothalamicgene expression of the leptin receptor downstream peptides neuropeptideY (NPY), proopiomelanocortin (POMC) and agouti-related peptide(AgRP) with their heterozygous Socs3 knock-out between wild-typeand knock-out mice after leptin infusion. This leads them tosuggest that other downstream peptides might be of relevancefor leptin action. In contrast, the complete Socs3 knock-outin brain tissue that is reached in experiments by Mori et al.(13) leads to an increase in hypothalamic POMC mRNA in contrastto wild-type animals 6 h after leptin infusion. This shows howimportant different approaches may be to elucidate the exactmechanisms of leptin action.

In summary, the papers of Howard et al. (12) and Mori et al.(13) add important new information on the physiology and pathophysiologyof leptin resistance in animals and potentially in man. Furtherexamination of the role of Socs3 in humans with leptin resistanceand the development of strategies to inhibit the action of hypothalamicSocs3 might provide a possible new target in the fight againstobesity.