The discovery and the characterization of the cannabinoid receptor 1 (CBR1) as well as the finding of its involvement in the regulation of satiety, has initiated the race for the development of antagonist molecules with the admitted purpose to counteract obesity. The first one which reach the clinical trials, was the SR141716, or Rimonabant, and a large number of studies were conducted with this molecule. The RIO, STRADIVARIUS, SERENADE and ADAGIO studies clearly showed that Rimonabant led to a loss of weight, an increase of HDL-C levels, a decrease of triglycerides and blood pressure, an improvement of the insulin response and glucose uptake, as well as an increase of adiponectin levels. Surprisingly, numerous effects of this molecule seem to be linked to a peripheral action. In particular, Rimonabant has a strong anti-inflammatory action on liver and on fat cells, which could explain its beneficial effects on the insulino-resistance. However, the molecule possesses major side effects, limitating its commercial development. These effects are inherent to the central action of the CBR1 antagonists. To eliminate these problems, it will be necessary to develop molecules which have only peripheral effects. Beside this, other molecules with a more important fat specificity could be of a strong interest, such as Cholesteryl Ester Transfert Protein (CETP) inhibitors. Indeed, this type of molecules gives good clinical results with no central effect. So, despite the commercial failure of Torcetrapib, it is likely that we will see the development of several molecules targeting CETP and yet with limited side effects.
Obesity is a challenging health problem in the industrialized world and in recent population studies the prevalence of overweight, obesity and abdominal obesity is constantly increasing, reaching to an epidemic proportions. The excess of body weight is associated with a low-grade systemic inflammation and a cluster of metabolic alterations such as insulin resistance, hypertension and dyslipidemia, which is presumed to play a role in the development of cardiovascular disease and type 2 diabetes mellitus. It is now well-established that adipocytes secrete proteins (adipokines) that actively control energy homeostasis, glucose and lipid metabolism, neuroendocrine and cardiovascular function and inflammatory response. Excessive levels of some adipokines such as TNF-α and IL-6 can disturb the metabolism suggesting the adipose tissue as a link between obesity, low grade inflammation and insulin resistance. In obesity, sustained weight loss has several beneficial effects on lipid metabolism, glucose tolerance and arterial blood pressure. There have been an increasing number of obese patients requiring treatment (bariatric surgery and/or diet) for weight loss. The weight loss induced by bariatric surgery causes a reduction in the inflammatory state, increasing levels of adiponectin and GLP-1, which are all related to beneficial metabolic changes described above. GLP-1 is especially related to insulinotropic properties through induced expansion of insulin secreting B-cell mass and enhanced insulin secretion. GLP-1 acts also in insulin action enhancing B-cell glucose sensitivity contributing to glycemic control after surgical procedure. So our focus in this chapter is to emphasize metabolic and inflammatory profile in obesity and its metabolic changes after weight loss.