The b₃ adrenoceptor has a profile quite distinct from that of b₁ and b₂ adrenergic receptors. Rodents, humans and other mammals share many of the characteristic b₃ properties, although observable species-species differences have been identified. The naturally occurring variant of the human b₃ receptor was correlated with hereditary obesity in Pima Indians, in Japanese individuals and in Western obese patients. Weight gain was also observed in female mice whose b₃ gene had been disrupted.

These examples provided a picture of the important role of the b₃ receptor in the regulation of lipid metabolism and as a possible target for drugs to treat certain forms of obesity.

Early antagonist/agonist studies of b adrenergic receptors suggested the existence of atypical responses clearly different from effects mediated by the b₁ and b₂ adrenoceptors. The new agonist BR37344 stimulated lipolysis in rodent brown adipocytes even in the presence of the antagonist propranolol. This and other discoveries led to the notion that additional receptors existed in fat, in the gut, in the heart and possibly in skeletal muscle. Cloning, sequencing and expression of the b₃ gene in various species has now served to confirm the existence of this receptor.

The b₃ adrenoceptor is composed of a single 408 amino acid residue peptide chain that belongs to the family of G-protein coupled receptors. The G-protein receptors are characterised by seven hydrophobic stretches of about 22 to 28 residues forming seven transmembrane segments. The transmembrane (TM) regions are linked with three intracellular and three extracellular loops. The amino acid (N) terminal of these receptors is located extacellularly and is glycosylated. The carboxy (C) terminal is intracellular and the case of the b₃ receptors does not have any phosphorylation sites.

Comparison of the b receptor subtypes revealed that there were a limited number of conserved residues and these were mainly restricted to the transmembrane segments and to the proximal regions of the intracellular loops.

Comparing b₃ with b₃ receptors of other species revealed a high degree of sequence homology approximately 80-90% between human, bovine, rodent and canine. The human, monkey and bovine b₃ receptors are closer to each other than any of the rodents sequences, in particular in transmembrane segment one. Closer inspection of the various b₃ sequences revealed that the human b₃ is distinct from is animal relatives in several positions occupied by one type of residue in humans and another type in animals. One particular example of this occurs in position 64, which is occupied in humans by a tryptophan residue and an arginine in all other species.

Computer modelling has defined an image of the b₃ ligand-binding site. At least four of the seven transmembrane domains are essential for ligand binding (see diagram below). The amino acids that are involved were identified by site-directed mutagenesis and photoaffinty labelling these are Asp¹¹⁷ in TM3, a residue found to be essential for binding all biogenic amines. Ser¹⁶⁹ in TM4, is thought to form a hydrogen bonds with the hydroxyl of the ethanolamine side-chain. Ser²⁰⁹ and Ser²¹² in TM5, also located in many biogenic amine receptors, are thought to form hydrogen bonds with the hydroxyls of the catechol side chain. Also Phe³⁰⁹ in TM6, involved in hydrophobic interactions with the aromatic ring of catecholamines. Two of the three TM domains are involved in G_s activation, TM2, which contain Asp⁸³, and TM7, which contains Tyr³³⁶.

Attempts to explain why several b₂ antagonists behave as b₃ agonist have not yet been successful. b₃ receptors appear to contain less bulky residues, and could therefore accommodate the larger b₁/b₂ antagonists. Mutagenesis has been used to substitute the small Gly residue with the larger Phe residue at position 53 in the b₃ receptor; this change however was not enough to convert the b₃ agonist to an antagonist.

The Gs interaction site on b₃ is situated in the intracellular region, mainly the membrane proximal regions of the second and third (i2, i3) intracellular loops and the carboxy-terminal domains. Deletion of small segments of the amino terminal and carboxy terminal regions of the i3 of the b₃ receptor uncoupled the human receptor from adenylate cyclase upon agonist stimulation.

Several reports propose that the b₃ receptor may be coupled to more than one second messenger system. It has been shown that b₃ receptors in rat adipocytes interact with both Gs and Gi proteins. The b₃ adrenergic receptor in the septum of the human heart has also been reported to link with the Gi protein, resulting in a negative inotropic effect. This is in contrast to previous observations that always associated b receptors with positive inotropism in the heart.

b₃ adrenoceptors are primarily expressed in brown and white adipose tissue (BAT and WAT), where it is thought to regulate noradrenaline-induced changes in energy metabolism and thermogenesis. Several reports have also indicated the existence of b₃ receptors in additional locations, where the receptor may modulate other functions. As is the case of the gastro-intestinal tract where b₃ may modulate intestinal motility by causing vaso-relaxation or protect the mucosal surface. Expression of b₃-like properties in cardiac tissue has also been well documented.

The evidence in support of the b₃ adrenergic receptor modulating energy metabolism and thermogenesis comes from studies on rodents where b₃ agonists considerably reduced diet-induced obesity. Evidence was also collected from experiments carried out in adult dogs treated with b₃ agonist ICI D7114 for two month, the dogs showed a reduction in weight and also showed an increase in BAT (the tissue mostly responsible for thermogenesis normally undetected in adult mammals other than rodents).

The role of the b₃ receptor in adipocytes is now well-documented in rodents, where it is the main subtype in white and brown adipocytes. In these cells the b₃ is coupled to adenylate cyclase III, stimulation of which generates cAMP that phosphorylates the hormone sensitive protein lipoprotein lipase responsible for lipolysis of triglycerides. In white adipocytes, the resulting free fatty acids are either released in serum or reassembled in triglycerides. In brown adipocytes the free fatty acids are oxidised into CO₂ and water releasing energy in the form of heat.

Due this role in fat metabolism in rodents and its predominant expression in human fat tissues the b₃ receptor in now widely considered a valuable pharmacological target for the treatment of obesity. The development of a selective b₃ agonist therefore constitutes the most realistic approach to a useful agent for the treatment of human obesity. Such a compound, rather than support an effort to inhibit appetite, would help reduce accumulated fat rendering this approach more attractive.