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Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome
Journal article   Open access   Peer reviewed

Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome

Kamal Rahmouni, Melissa A Fath, Seongjin Seo, Daniel R Thedens, Christopher J Berry, Robert Weiss, Darryl Y Nishimura and Val C Sheffield
The Journal of clinical investigation, Vol.118(4), pp.1458-1467
04/2008
DOI: 10.1172/JCI32357
PMCID: PMC2262028
PMID: 18317593
url
https://doi.org/10.1172/JCI32357View
Published (Version of record) Open Access

Abstract

Bardet-Biedl syndrome (BBS) is a heterogeneous genetic disorder characterized by many features, including obesity and cardiovascular disease. We previously developed knockout mouse models of 3 BBS genes: BBS2, BBS4, and BBS6. To dissect the mechanisms involved in the metabolic disorders associated with BBS, we assessed the development of obesity in these mouse models and found that BBS-null mice were hyperphagic, had low locomotor activity, and had elevated circulating levels of the hormone leptin. The effect of exogenous leptin on body weight and food intake was attenuated in BBS mice, which suggests that leptin resistance may contribute to hyperleptinemia. In other mouse models of obesity, leptin resistance may be selective rather than systemic; although mice became resistant to leptin's anorectic effects, the ability to increase renal sympathetic nerve activity (SNA) was preserved. Although all 3 of the BBS mouse models were similarly resistant to leptin, the sensitivity of renal SNA to leptin was maintained in Bbs4 -/- and Bbs6 -/- mice, but not in Bbs2 -/- mice. Consequently, Bbs4 -/- and Bbs6 -/- mice had higher baseline renal SNA and arterial pressure and a greater reduction in arterial pressure in response to ganglionic blockade. Furthermore, we found that BBS mice had a decreased hypothalamic expression of proopiomelanocortin, which suggests that BBS genes play an important role in maintaining leptin sensitivity in proopiomelanocortin neurons.
 Magnetic Resonance Imaging Molecular Chaperones - metabolism Bardet-Biedl Syndrome - metabolism Microtubule-Associated Proteins - genetics Microtubule-Associated Proteins - metabolism Body Weight - drug effects Group II Chaperonins Obesity - genetics Bardet-Biedl Syndrome - pathology Electrocardiography Bardet-Biedl Syndrome - genetics Leptin - pharmacology Hypertension - genetics Microtubule-Associated Proteins - deficiency Disease Models, Animal Molecular Chaperones - genetics Organ Size Blood-Brain Barrier - drug effects Hypertension - metabolism Mice, Knockout Obesity - metabolism Gene Expression Regulation - drug effects Proteins - genetics Animals Proteins - metabolism Mice

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