Current and future drug targets in weight management
Witkamp, R.F. - \ 2011
Pharmaceutical Research 28 (2011)8. - ISSN 0724-8741 - p. 1792 - 1818.
11-beta-hydroxysteroid dehydrogenase type-1 - protein-coupled receptor - cannabinoid cb1 receptor - brown adipose-tissue - placebo-controlled trial - histamine h3 receptor - food-intake - metabolic-disorders - endocannabinoid system - energy-expenditure
Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbidity figures and a shortage of effective drugs have generated substantial research activity with several molecular targets being investigated. However, pharmacological modulation of body weight is extremely complex, since it is essentially a battle against one of the strongest human instincts and highly efficient mechanisms of energy uptake and storage. This review provides an overview of the different molecular strategies intended to lower body weight or adipose tissue mass. Weight-loss drugs in development include molecules intended to reduce the absorption of lipids from the GI tract, various ways to limit food intake, and compounds that increase energy expenditure or reduce adipose tissue size. A number of new preparations, including combinations of the existing drugs topiramate plus phentermine, bupropion plus naltrexone, and the selective 5-HT2C agonist lorcaserin have recently been filed for approval. Behind these leading candidates are several other potentially promising compounds and combinations currently undergoing phase II and III testing. Some interesting targets further on the horizon are also discussed
Adipose gene expression patterns of weight gain suggest counteracting steroid hormone synthesis
Schothorst, E.M. van; Franssen-Hal, N.L.W. van; Schaap, M.M. ; Pennings, J. ; Hoebee, B. ; Keijer, J. - \ 2005
Obesity Research 13 (2005)6. - ISSN 1071-7323 - p. 1031 - 1041.
11-beta-hydroxysteroid dehydrogenase type-1 - c57bl/6j mice - high-fat - obesity - tissue - microarray - adipogenesis - metabolism - humans - alpha
VAN SCHOTHORST, EVERT M., NICOLE FRANSSEN-VAN HAL, MIRJAM M. SCHAAP, JEROEN PENNINGS, BARBARA HOEBEE, AND JAAP KEIJER. Adipose gene expression patterns of weight gain suggest counteracting steroid hormone synthesis. Obes Res. 2005;13:1031-1041. Objective: To identify early molecular changes in weight gain, using analysis of gene expression changes in adipose tissue of mice fed well-defined humanized (Western) high-fat and low-fat (control) diets during a short (3- to 5-week) time interval. Research Methods and Procedures: An adipose-enriched cDNA microarray was constructed and used for the expression analyses of visceral adipose tissues of wildtype young adult C57BL/6J male mice on different diets. Results: Mice on a high-fat diet had significantly higher body weight (at most, 9.6% greater) and adipose tissue weights compared with mice on a control diet. Gene expression analyses revealed 31 transcripts significantly differentially expressed in visceral adipose tissue between the diet groups. Most of these genes were expressed more on the high-fat diet. They mainly encode proteins involved in cellular structure (e.g., myosin, procollagen, vimentin) and lipid metabolism (e.g., leptin, lipoprotein lipase, carbonic anhydrase 3). This increase in gene expression was accompanied by a decrease in oxidative phosphorylation and carbohydrate metabolism (ATP citrate lyase). Importantly, genes belonging to steroid hormone biosynthesis (3 beta-hydroxysteroid dehydrogenase-1, cholesterol side-chain cleavage cytochrome P450, and steroid-11 beta-hydroxylase) were all expressed less in mice on a high-fat diet. Discussion: A short time period of 3 to 5 weeks of high-fat feeding altered gene expression patterns in visceral adipose tissue in male mice. Gene expression changes indicate initiation of adipose tissue enlargement and the down-regulation of adipose steroid hormone biosynthesis. The latter suggests a mechanism by which initial progression toward weight gain is counteracted.