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Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3


Leptin is an adipocyte-derived hormone that regulates energy balance and neuroendocrine function primarily by acting on specific hypothalamic pathways1,2. Resistance to the weight reducing effects of leptin is a feature of most cases of human and rodent obesity1,2, yet the molecular basis of leptin resistance is poorly understood. We have previously identified suppressor of cytokine signaling-3 (Socs3) as a leptin-induced negative regulator of leptin receptor signaling and potential mediator of leptin resistance3,4,5. However, due to the non-viability of mice with targeted disruption of Socs3 (ref. 6), the importance of Socs3 in leptin action in vivo was unclear. To determine the functional significance of Socs3 in energy balance in vivo we undertook studies in mice with heterozygous Socs3 deficiency (Socs3+/−). We report here that Socs3+/− mice display greater leptin sensitivity than wild-type control mice: Socs3+/− mice show both enhanced weight loss and increased hypothalamic leptin receptor signaling in response to exogenous leptin administration. Furthermore, Socs3+/− mice are significantly protected against the development of diet-induced obesity and associated metabolic complications. The level of Socs3 expression is thus a critical determinant of leptin sensitivity and obesity susceptibility in vivo and this molecule is a potential target for therapeutic intervention.

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Figure 1: Enhanced weight-reducing effect of exogenous leptin in Socs3+/− mice.
Figure 2: Enhanced hypothalamic leptin-mediated Stat3 phosphorylation in Socs3+/− mice.
Figure 3: Protection against diet-induced obesity and improved metabolic parameters in mixed background Socs3+/− mice.
Figure 4: Attenuation of diet-induced obesity and enhanced insulin sensitivity in C57Bl/6 Socs3+/− mice.

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Funded by grants from the National Institutes of Health (to J.S.F and C.B.), Takeda Chemical Industries (to J.S.F.), The Wellcome Trust, UK and the Royal College of Physicians, UK (to J.K.H.) and the Sigrid Jusélius Foundation (to L.J.O.). We thank J. Ihle for access to the Socs3+/− mice and H. Shi, K. Inouye and P. Pissios for their assistance in aspects of these studies.

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Correspondence to Jeffrey S Flier.

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The authors declare no competing financial interests.

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Supplementary Fig. 1

Food intake and hypothalamic neuropeptides in leptin-infused wild-type and Socs3+/− mice. (PDF 14 kb)

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Howard, J., Cave, B., Oksanen, L. et al. Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3. Nat Med 10, 734–738 (2004).

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