Endocrine Abstracts (2003) 6 S14

Brain melanocortin receptors - feeding and energy expenditure

C Small

Department of Metabolic Medicine, Imperial College, Hammersmith Hospital, London, UK.

The hypothalamic melanocortin system consists of an endogenous antagonist, agouti related protein (Agrp) and agonist, alpha-melanocyte stimulating hormone (alpha-MSH), which act at the hypothalamic melanocortin 3 and 4 receptors. CNS administration of Agrp increased food intake over a 24-h period. Agrp blocked the reduction in 1-h food intake observed following alpha-MSH administration. This effect occurred independently of whether the antagonist was administered simultaneously, or nine hours prior, to the alpha-MSH. Prolonged fasting is associated with a down regulation of the hypothalamo-pituitary thyroid axis. ICV or Intraparaventricular nuclear administration of Agrp produced a long lasting suppression of plasma TSH and T4. ICV administration of alpha-MSH increased plasma TSH in 24h fasted rats. In vitro, alpha-MSH increased TRH release from hypothalamic explants. Agrp alone caused no change in TRH release but antagonised the effect of alpha-MSH. Leptin increased TRH release from hypothalami harvested from 48h fasted rats. Agrp blocked this effect. This work was further expanded to examine the effect of chronic ICV Agrp treatment on energy metabolism in both ad libitum fed rats and rats administered Agrp then pair fed to the saline control group. Chronic Agrp administration increased food intake and body weight in ad libitum fed animals and was associated with an increased fat mass and plasma leptin. In the Agrp treated pair fed group a significant increase in the fat mass and plasma leptin was again observed, suggesting that Agrp caused metabolic changes independently of increased food intake. BAT UCP-1 and plasma TSH were significantly decreased in both the Agrp ad libitum and pair-fed groups. In addition, chronic Agrp treatment decreased oxygen consumption. These studies demonstrate that the hypothalamic melanocortin system is not only an important regulator of food intake but influences thyroid function and energy expenditure.

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