β3-Adrenergic Receptors: Really Relevant Targets for Anti-Obesity Drugs?

E.      Nisoli; C.      Tonello; M.   O.   Carruba

Abstract

In simple terms, obesity is a chronic disorder of energy imbalance, for which a long-term excess of energy intake over expenditure leads to the storage of that excess energy as white adipose tissue. In this article, we review β3- adrenergic receptor agonists, agents in development both to increase energy expenditure and counteract energy expenditure decline following a calorie restriction program. β3- adrenergic receptor agonists are very effective thermogenic anti-obesity and insulin-sensitising agents in rodents. Their main sites of action are white and brown adipose tissue, and muscle. β3-adrenergic receptor mRNA levels are lower in human than in rodent adipose tissue, and adult humans have little brown adipose tissue. Nevertheless, β3-adrenergic receptors are expressed in human white as well as brown adipose tissue and in skeletal muscle, and they play a role in the regulation of energy balance and glucose homeostasis. It is difficult to identify β3-adrenergic receptor agonist drugs because the pharmacology of both β3- and β1- adrenergic receptors can vary. Since their discovery in 1983, hundreds different compounds have been synthesized with β3-adrenergic receptor agonist profile. We identified in the literature 32 molecules in development: 9 molecules are in discovery phase (from 10 October 2001 to 25 November 2002: five molecules in 2002 and 4 in 2001), 5 molecules are in different clinical phases, 10 molecules were discontinued, for 8 molecules no development was reported. Here we have tried to demonstrate that the preclinical and clinical studies on b3-adrenergic receptors and b3-adrenergic receptor agonists as anti-obesity drugs is yet active, even if no conclusive therapeutic agents have been identified. With the huge recent increase in our knowledge on the molecular processes involved in adipose cell biology and adaptive thermogenesis, there may yet be a future for b3-adrenergic receptor agonists.

Keywords: adrenergic receptor, adrenergic receptor agonists, thermogenic drugs, energy balance, obesity, brown adipose tissue

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