Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome.
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.
Rahmouni
Kamal
K
Department of Internal Medicine, Center on Functional Genomics of Hypertension, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA. kamal-rahmouni@uiowa.edu
Fath
Melissa A
MA
Seo
Seongjin
S
Thedens
Daniel R
DR
Berry
Christopher J
CJ
Weiss
Robert
R
Nishimura
Darryl Y
DY
Sheffield
Val C
VC
D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001812:Blood-Brain Barrier / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004562:Electrocardiography; D005786:Gene Expression Regulation / Q000187:drug effects; D056385:Group II Chaperonins; D006973:Hypertension / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size; D011506:Proteins / Q000235:genetics / Q000378:metabolism*
C506281:BBS4 protein, mouse; C528012:Bbs2 protein, mouse; D020738:Leptin; D008869:Microtubule-Associated Proteins; C506279:Mkks protein, mouse; D018832:Molecular Chaperones; D011506:Proteins; C110856:proteasome maturation protein; D056385:Group II Chaperonins