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Pathophysiological mechanisms of obesity and hypertension in mouse models of Bardet‐Biedl syndrome
Author(s) -
Rahmouni Kamal,
Fath Melissa A,
Andrews Mike,
Sigmund Curt D.,
Sheffield Val C.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1207
Subject(s) - bardet–biedl syndrome , endocrinology , medicine , leptin , obesity , knockout mouse , metabolic syndrome , blood pressure , polydactyly , biology , phenotype , anatomy , receptor , gene , biochemistry
Bardet‐Biedl syndrome (BBS) is a genetic disorder with the cardinal features of obesity, retinopathy and polydactyly. We have developed mouse BBS models for BBS2, BBS4 and BBS6 whose phenotypes closely resemble that of humans. We sought to use these models to dissect the mechanisms involved in the metabolic and cardiovascular disorders associated with BBS. We found that BBS null mice develop obesity due to both hyperphagia and decrease activity. Obesity in the BBS knockout mice is associated with high circulating levels of the adipocyte‐derived hormone, leptin even at an early age (5–6 weeks old) when no difference in body weight could be detected. Administration of exogenous leptin caused a significant decrease in body weight and food intake in the wild type mice, but leptin failed to reduce appetite or body weight in Bbs2−/ −, Bbs4−/ − and Bbs6−/ −mice. This indicates that loss of leptin action in the central nervous system may be important for the development of obesity associated with BBS. Next we compared arterial pressure between wild type and BBS null mice. Bbs4−/ − and Bbs6−/ − mice exhibited ~12 mmHg higher arterial pressure than their wild type controls. However, Bbs2−/ − mice had normal arterial pressure. Increased sympathetic nerve activity (SNA) is considered to be an important mechanism of obesity‐associated hypertension. Using multifiber recording, we found that Bbs4v/− and Bbs6−/ − mice have higher baseline renal SNA as compared to the wild type mice but the Bbs2−/ − mice did not, consistent with the normal arterial pressure findings. All 3 mouse models of BBS exhibit obesity however only 2 exhibit hypertension. Our data also suggest a role for the renal SNA in the hypertension associated with BBS.