Sympathetic innervation and the development of structure and function of brown adipose tissue: studies on lambs chemically sympathectomized in utero with 6-hydroxydopamine.

Fetal sheep were injected intramuscularly with 25-100 mg/kg of 6-hydroxydopamine HBr on 3-4 occasions between the 94th and 136th day of pregnancy. Following birth, which took place normally, the metabolic response to cold (summit metabolism) was found to be lower in treated than in control lambs, by an amount that approximated the thermogenic potential of brown fat. Under thermo-neutral conditions, the dose of infused noradrenaline (10 microgram kg-1 min-1) that stimulates maximum non-shivering thermogenesis in control lambs failed to stimulate thermogenesis in treated lambs unless accompanied by a dose of the alpha-blocker, phentolamine. This failure was apparently due to vasoconstriction induced by hypersensitivity to noradrenaline; hypersensitivity was also indicated when one-tenth of this dose was found to be fully effective in stimulating metabolism and substrate mobilization of the treated lambs. Examination of the perirenal adipose tissue of treated lambs with the electron microscope and by a monoamine fluorescence technique that visualizes catecholamine-containing structures, revealed that the tissue possessed the histological characteristics of brown fat, but there was little or no evidence of sympathetic innervation, in contrast with profuse innervation in control lambs. This is consistent with the observed hypersensitivity to noradrenaline. Similar histological findings were made in lambs that had received weekly intraperitoneal injections of 6-hydroxydopamine from day 70 of gestation, after which time sympathetic innervation normally begins to appear. It is probable that an intact sympathetic innervation is unnecessary for normal development of brown adipose tissue. This chemical sympathectomy appears to be long-lasting since treated lambs 8-months old were unable to vasoconstrict their extremities effectively in response to cold, and significant monoamine fluorescence could not be demonstrated in the various tissues examined.