Drugs that Block Fat Cell Formation

The adipose tissue is a specialized conjunctive tissue with a predominance of the cell type called adipocyte. Their main function is to store energy as triacylglycerides (TGs). The energy-storing function of adipose tissue is highly efficient due to the low density and high caloric value of TGs. The adipose tissue is also important for temperature isolation, for structural [Page 201]support of organs, and for a recently discovered endocrine function. Adipose tissue metabolism is very active, involving multiple processes including lipogenesis, lipolysis, and adipogenesis, which are under dynamic equilibrium. Adipogenesis is the differentiation process by which preadipocyte cells mature into adipocytes. Lipolysis is a catabolic pathway, whereby stored TGs are metabolized to yield free fatty acids (FFAs) and glycerol with subsequent oxidation of FFAs for energy production.

Lipogenesis is the process of storing energy in the form of TGs into the adipocyte. In this case, FFAs are re-esterified to yield TGs. The occurrence of lipogenesis in the adipocytes requires glucose intake, which can be transformed into glycerol phosphate. The necessary FFAs for lipogenesis usually come from the diet. However, they can also be synthesized from glucose incoming into the adipocyte, with the participation of the enzyme fatty acid synthase (FAS) in a process called lipogenesis de novo. Although not a major process, it also takes place in the adipocyte. Lipid metabolism of adipose cells is modulated by the intracellular protein kinases pathway, which is initiated by activation of membrane receptors, inducing internal signaling cascades that ultimately result in the activation or inhibition of catabolic and anabolic pathways.

Because obesity is the storage of excess energy, reduction of body fat can be achieved either by reducing food (energy) intake or by increasing energy expenditure. A new approach for the treatment and prophylaxis of obesity may be based on the inhibition of carbonic anhydrase (CA), enzymes involved in several steps of de novo lipogenesis, both in the mitochondria and the cytosol of cells. Topiramate and zonisamide, clinically used antiepileptic drugs also showing strong CA inhibitory properties, possess a very much desired side effect in obese patients, that is, induction of weight loss. Indeed, it has been recently proven that both topiramate as well as zonisamide act as very potent in vitro inhibitors of several CA isozymes (including CA II, CA VA, and CA VB), and that this might explain their antiobesity effects. Furthermore, it was also demonstrated that inhibition of CA by trifluoromethanesulfonamide (TFM) or acetazolamide can decrease lipogenesis in adipocytes in cell culture. Acetazolamide is a clinically used drug that has been shown to reduce intraocular pressure and is used as an adjunct to other agents in the treatment of glaucoma. This seems to be the beginning of a very new and promising approach for the treatment of obesity, with the hope that more compounds showing this property will be soon developed and available for clinical use.

A number of in vitro studies have also examined the effects of human immunodeficiency virus (HIV) protease inhibitors (PIs) on murine and human adipocyte differentiation. These studies indicate that different PIs have different effects on adipocyte function and differentiation. Adipogenesis of human mesenchymal stem cells (hMSCs) was strongly inhibited by saquinavir and nelfinavir ex vivo.

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