Beta-Adrenergic receptor modulation of adipocyte metabolism and growth

Abstract

Abstract β -Adrenergic receptor ( β AR) agonists reduce body fat in mammals and birds. Synthetic lipid metabolism is decreased in β AR agonist-treated animals or in agonist-treated adipocytes in vitro. Degradative lipid metabolism is increased by β AR agonists in adipocytes in vitro and in vivo. The β AR agonist effects are blocked by β AR antagonists. In mammalian tissues, there are at least three distinct β AR subtypes; β -1 ( β 1AR), β -2 ( β 2AR), and β -3 ( β 3AR). Individual tissues have different proportions of subtypes. For example, greater than 85% of the β AR in rat heart is β 1AR, in guinea pig lung is β 2AR, and in rat adipose tissue is β 3AR. Subtype distribution within a tissue varies with species (e.g., human heart has 65% β 1AR and porcine adipocytes have less than 10% β 3AR). There is species variation in the amino acid sequence of a β AR subtype. Thus, it is expected that some β AR agonists would have different effects in the same tissue in different species because of different β AR subtype distribution and(or) amino acid sequence. In support of these concepts, the pharmacology of β AR agonists and antagonists in adipocytes is in many cases species-specific. Cloning of individual β AR subtypes allows determination of the pharmacology of subtypes from that species. For example, the pharmacology of the cloned porcine β 1AR, β 2AR, and β 3AR indicates selected agonists or antagonists can be used to assess the proportion of β AR subtypes. Nucleic acid sequences of the subtypes were used to prepare probes to quantify the subtype mRNA. The pharmacological and mRNA data agree rather closely and indicate porcine adipocytes contain over 70% β 1AR. The effects produced by a β AR agonist (or antagonist) on adipose tissue in vivo depend not only on the species and the adipocyte β AR subtype distribution, but also on the pharmacokinetics and pharmacodynamics of the compound in that species, including blood flow to the tissue, and the multiple metabolic and endocrine effects of the compound in other tissues of the body. In short, it is expected that individual β AR agonists would have somewhat different effects in different species.