Metabolic relationships between lipolysis and respiration in rat brown adipocytes. The role of long chain fatty acids as regulators of mitochondrial respiration and feedback inhibitors of lipolysis.

The calorigenic action of norepinephrine in isolated brown adipocytes was selectively mimicked by theophylline, dibutyryl cyclic AMP, and the principal fatty acids known to be present in the acyl moieties of brown adipose tissue triglycerides (palmitic, oleic, and linoleic acids). The stimulatory effects of fatty acids were entirely reversible, occurred at physiological concentrations, and were critically dependent upon the molar ratio of extracellular fatty acids to albumin. The calorigenic potency of fatty acids increased with their chain length. The apparent synchrony between the switching "on and off" of lipolysis and respiration by norepinephrine and propranolol indicated that the two phenomena are functionally inter-related and that they are both mediated by beta-adrenoreceptors. Respiratory stimulation by palmitic acid was accompanied by an inhibition of glycerol release suggesting that fatty acids retroinhibit lipolysis while simultaneously activating respiration. Studies with 2-tetradecylglycidic acid, oligomycin, and uncouplers of oxidative phosphorylation support the view that fatty acids exert their calorigenic effects by increasing mitochondrial proton permeability and by simultaneously serving as substrates for beta-oxidation via carnitine-dependent pathways. Since fatty acids mimicked the calorigenic action of norepinephrine even when beta-adrenoreceptors were blocked by propranolol, it is concluded that cyclic AMP controls respiration indirectly, most probably by modulating lipolysis. It is suggested that endogenous long chain fatty acids released in consequence of cyclic AMP activation of lipolysis play a fundamental role in the control of brown adipose tissue metabolism by self-regulating lipolysis and by serving as physiological modulators of mitochondrial oxygen consumption.