Hypothalamic Regulation of Adiposity: The Role of 11β-Hydroxysteroid Dehydrogenase Type 1

Abstract

Following extensive suprasellar operations for excision of hypothalamic tumors, some patients develop morbid obesity despite receiving replacement doses of glucocorticoids. Urine analysis of cortisol and cortisone metabolites show that 11-OH/11-oxo ratios are significantly higher in patients with hypothalamic obesity, indicating enhanced 11β-HSD1 activity. This correlates with the visceral-to-subcutaneous fat ratio. The consequence of increased 11β-HSD1 activity and a shift of the steroid inter-conversion towards cortisol may contribute to the effects of the latter in adipose tissue. The message from the hypothalamus to adipocyte 11β-HSD-1 involves hormones, the sympathetic nervous system and cytokines. CRH and ACTH downregulate 11β-HSD-1 activity and induce lipolysis. Tumor necrosis factor-α and interleukin-1β upregulate 11β-HSD-1 expression and activity, while enhancing lipolysis. The sympathetic nervous system exerts its effects through β-adrenergic upregulation and α-adrenergic downregulation of 11β-HSD-1 activity. Inhibition of 11β-HSD-1 suppresses preadipocyte differentiation into mature adipocytes, and may provide a therapeutic tool.

Key words

Hypothalamus - Obesity - 11β-hydroxysteroid dehydrogenase - Adipocyte

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