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Deficiency and inhibition of cathepsin K reduce body weight gain and increase glucose metabolism in mice.

ABSTRACT: Previous studies demonstrated increased levels of cysteine proteases cathepsins in serum and adipose tissues from obese patients. We now provide evidence from a mouse model of obesity to suggest a direct participation of cathepsin K (CatK) in mouse body weight gain and glucose metabolism.Using real-time polymerase chain reaction, we detected 12-fold increase in CatK transcripts after adipogenesis of human preadipocytes. Using an immunohistology analysis, we consistently observed high levels of CatK expression in adipose tissues from obese humans and mice. Selective inhibition of CatK activity blocked the lipid accumulation in human and mouse preadipocytes. In mice, CatK deficiency reduced significantly diet-induced body weight gain and serum glucose and insulin levels. Similar results were obtained in diet-induced and genetically created (ob/ob) obese mice after animals were treated with a CatK-selective inhibitor. Mechanistic study demonstrated a role for CatK in degrading fibronectin, a matrix protein that controls adipogenesis. Deficiency or inhibition of CatK leads to fibronectin accumulation in muscle and adipose tissues.This study demonstrates an essential role of CatK in adipogenesis and mouse body weight gain, possibly via degradation of fibronectin, thus suggesting a novel therapeutic strategy for the control of obesity by regulating CatK activity.

SUBMITTER: Yang M

PROVIDER: S-EPMC2736686 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Deficiency and inhibition of cathepsin K reduce body weight gain and increase glucose metabolism in mice.

Yang Min M Sun Jiusong J Zhang Tinghu T Liu Jian J Zhang Jie J Shi Michael A MA Darakhshan Froogh F Guerre-Millo Michèle M Clement Karine K Gelb Bruce D BD Dolgnov Gregory G Shi Guo-Ping GP

Arteriosclerosis, thrombosis, and vascular biology 20080925 12

<h4>Objective</h4>Previous studies demonstrated increased levels of cysteine proteases cathepsins in serum and adipose tissues from obese patients. We now provide evidence from a mouse model of obesity to suggest a direct participation of cathepsin K (CatK) in mouse body weight gain and glucose metabolism.<h4>Methods and results</h4>Using real-time polymerase chain reaction, we detected 12-fold increase in CatK transcripts after adipogenesis of human preadipocytes. Using an immunohistology analy ...[more]

PMID: 18818416

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Project description:BACKGROUND:Weight gain is common for people with schizophrenia and this has serious implications for health and well being. OBJECTIVES:To determine the effects of both pharmacological (excluding medication switching) and non pharmacological strategies for reducing or preventing weight gain in people with schizophrenia. SEARCH STRATEGY:We searched key databases and the Cochrane Schizophrenia Group's trials register (April 2006), reference sections within relevant papers, hand searched key journals, and contacted the first author of each relevant study and other experts to collect further information. SELECTION CRITERIA:We included all clinical randomised controlled trials comparing any pharmacological or non pharmacological intervention for weight gain (diet and exercise counselling) with standard care or other treatments for people with schizophrenia or schizophrenia-like illnesses. DATA COLLECTION AND ANALYSIS:We reliably selected, quality assessed and extracted data from studies. As weight is a continuous outcome measurement, weighted mean differences (WMD) of the change from baseline were calculated. The primary outcome measure was weight loss. MAIN RESULTS:Twenty-three randomised controlled trials met the inclusion criteria for this review. Five trials assessed a cognitive/behavioural intervention and eighteen assessed a pharmacological adjunct. In terms of prevention, two cognitive/behavioural trials showed significant treatment effect (mean weight change) at end of treatment (n=104, 2 RCTs, WMD -3.38 kg CI -4.2 to -2.0). Pharmacological adjunct treatments were significant with a modest prevention of weight gain (n=274, 6 RCTs, WMD - 1.16 kg CI -1.9 to -0.4). In terms of treatments for weight loss, we found significantly greater weight reduction in the cognitive behavioural intervention group (n=129, 3 RCTs, WMD -1.69 kg CI -2.8 to -0.6) compared with standard care. AUTHORS' CONCLUSIONS:Modest weight loss can be achieved with selective pharmacological and non pharmacological interventions. However, interpretation is limited by the small number of studies, small sample size, short study duration and by variability of the interventions themselves, their intensity and duration. Future studies adequately powered, with longer treatment duration and rigorous methodology will be needed in further evaluating the efficacy and safety of weight loss interventions for moderating weight gain. At this stage, there is insufficient evidence to support the general use of pharmacological interventions for weight management in people with schizophrenia.

Dataset Information

Deficiency and inhibition of cathepsin K reduce body weight gain and increase glucose metabolism in mice.

Publications

Deficiency and inhibition of cathepsin K reduce body weight gain and increase glucose metabolism in mice.

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