Identification of SOCS-3 as a Potential Mediator of Central Leptin Resistance

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Molecular Cell (Impact Factor: 14.02). 04/1998; 1(4):619-25. DOI: 10.1016/S1097-2765(00)80062-3
Source: PubMed


Leptin affects food intake and body weight by actions on the hypothalamus. Although leptin resistance is common in obesity, mechanisms have not been identified. We examined the effect of leptin on expression of the suppressors-of-cytokine-signaling (SOCS) family of proteins. Peripheral leptin administration to ob/ob, but not db/db mice, rapidly induced SOCS-3 mRNA in hypothalamus, but had no effect on CIS, SOCS-1, or SOCS-2. A leptin-dependent increase of SOCS-3 mRNA was seen in areas of hypothalamus expressing high levels of the leptin receptor long form. In mammalian cell lines, SOCS-3, but not CIS or SOCS-2, blocked leptin-induced signal transduction. Expression of SOCS-3 mRNA in the arcuate and dorsomedial hypothalamic nuclei is increased in Ay/a mice, a model of leptin-resistant murine obesity. In conclusion, SOCS-3 is a leptin-inducible inhibitor of leptin signaling, and a potential mediator of leptin resistance in obesity.

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    • "to the SOCS protein family, which is rapidly induced by cytokines, and acts as an inhibitor of various cytokine signaling pathways. Previous studies have shown that SOCS3 is linked to phenotype by being a negative regulator of leptin[9,10]and insulin signaling[17,42,45]. In addition, there is evidence for association between variants located near SOCS3 with glucose homeostasis, BMI, and other obesity traits[50,51]. "
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    ABSTRACT: Background: The prevalence of type 2 diabetes (T2D) and obesity has dramatically increased within a few generations, reaching epidemic levels. In addition to genetic risk factors, epigenetic mechanisms triggered by changing environment are investigated for their role in the pathogenesis of these complex diseases. Epigenome-wide association studies (EWASs) have revealed significant associations of T2D, obesity, and BMI with DNA methylation. However, populations from the Middle East, where T2D and obesity rates are highest worldwide, have not been investigated so far. Methods: We performed the first EWAS in an Arab population with T2D and BMI and attempted to replicate 47 EWAS associations previously reported in Caucasians. We used the Illumina Infinium HumanMethylation450 BeadChip to quantify DNA methylation in whole blood DNA from 123 subjects of 15 multigenerational families from Qatar. To investigate the effect of differing genetic background and environment on the epigenetic associations, we further assessed the effect of replicated loci in 810 twins from UK. Results: Our EWAS suggested a novel association between T2D and cg06721411 (DQX1; p value = 1.18 × 10(-9)). We replicated in the Qatari population seven CpG associations with BMI (SOCS3, p value = 3.99 × 10(-6); SREBF1, p value = 4.33 × 10(-5); SBNO2, p value = 5.87 × 10(-5); CPT1A, p value = 7.99 × 10(-5); PRR5L, p value = 1.85 × 10(-4); cg03078551, intergenic region on chromosome 17; p value = 1.00 × 10(-3); LY6G6E, p value = 1.10 × 10(-3)) and one with T2D (TXNIP, p value = 2.46 × 10(-5)). All the associations were further confirmed in the UK cohort for both BMI and T2D. Meta-analysis increased the significance of the observed associations and revealed strong heterogeneity of the effect sizes (apart from CPT1A), although associations at these loci showed concordant direction in the two populations. Conclusions: Our study replicated eight known CpG associations with T2D or BMI in an Arab population. Heterogeneity of the effects at all loci except CPT1A between the Qatari and UK studies suggests that the underlying mechanisms might depend on genetic background and environmental pressure. Our EWAS results provide a basis for comparison with other ethnicities.
    Full-text · Article · Dec 2016
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    • "However, the mechanisms mediating leptin resistance are incompletely understood. To date, studies suggest that high blood leptin concentrations result in saturation of leptin transport across the blood brain barrier (blood brain barrier resistance) (Banks & Lebel 2002) and/or down regulation of leptin signaling in the hypothalamus due to constitutive expression of suppressor of cytokine signaling (hypothalamic resistance ) (Bjorbaek et al. 1998). "
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    ABSTRACT: Excessive weight gain in adults is associated with a variety of negative health outcomes. Unfortunately, dieting, exercise, and pharmacological interventions have had limited long-term success in weight control and can result in detrimental side effects, including accelerating age-related cancellous bone loss. We investigated the efficacy of using hypothalamic leptin gene therapy as an alternative method for reducing weight in skeletally-mature (9-month-old) female rats and determined the impact of leptin-induced weight loss on bone mass, density, and microarchitecture, and serum biomarkers of bone turnover (CTx and osteocalcin). Rats were implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either recombinant adeno-associated virus encoding the gene for rat leptin (rAAV-Leptin, n=7) or a control vector encoding green fluorescent protein (rAAV-GFP, n=10) and sacrificed 18 weeks later. A baseline control group (n=7) was sacrificed at vector administration. rAAV-Leptin-treated rats lost weight (-4±2%) while rAAV-GFP-treated rats gained weight (14±2%) during the study. At study termination, rAAV-Leptin-treated rats weighed 17% less than rAAV-GFP-treated rats and had lower abdominal white adipose tissue weight (-80%), serum leptin (-77%), and serum IGF1 (-34%). Cancellous bone volume fraction in distal femur metaphysis and epiphysis, and in lumbar vertebra tended to be lower (p<0.1) in rAAV-GFP-treated rats (13.5-months-old) compared to baseline control rats (9-months-old). Significant differences in cancellous bone or biomarkers of bone turnover were not detected between rAAV-Leptin and rAAV-GFP rats. In summary, rAAV-Leptin-treated rats maintained a lower body weight compared to baseline and rAAV-GFP-treated rats with minimal effects on bone mass, density, microarchitecture, or biochemical markers of bone turnover.
    Full-text · Article · Oct 2015 · Journal of Endocrinology
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    • "The adipocyte-derived hormone leptin is a pleiotropic hormone that affects multiple physiological processes, including appetite, body weight, neuroendocrine function, and emotional behaviors (Bjorbaek et al., 1998;Friedman and Halaas, 1998;Schwartz et al., 2000;Lu et al., 2006;Lu, 2007;Liu et al., 2010Liu et al., , 2011Guo et al., 2012Guo et al., , 2013Guo and Lu, 2014;Wang et al., 2015). Previous studies have shown that systemic administration of leptin elicits anxiolytic-like effects in mice (Liu et al., 2010) and rats (Haque et al., 2013). "

    Preview · Article · Oct 2015 · The International Journal of Neuropsychopharmacology
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