Hypothalamic regulation of adiposity: the role of 11beta-hydroxysteroid dehydrogenase type 1.
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 11beta-HSD1 activity. This correlates with the visceral-to-subcutaneous fat ratio. The consequence of increased 11beta-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 11beta-HSD-1 involves hormones, the sympathetic nervous system and cytokines. CRH and ACTH downregulate 11beta-HSD-1 activity and induce lipolysis. Tumor necrosis factor-alpha and interleukin-1beta upregulate 11beta-HSD-1 expression and activity, while enhancing lipolysis. The sympathetic nervous system exerts its effects through beta-adrenergic upregulation and alpha-adrenergic downregulation of 11beta-HSD-1 activity. Inhibition of 11beta-HSD-1 suppresses preadipocyte differentiation into mature adipocytes, and may provide a therapeutic tool.
Hochberg
Z
Z
Division of Endocrinology, Meyer Children's Hospital, PO Box 9602, Rambam Medical Center, Haifa 31096, Israel. z_hochberg@rambam.health.gov.il
Friedberg
M
M
Yaniv
L
L
Bader
T
T
Tiosano
D
D
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000031:analogs & derivatives* / Q000378:metabolism*; D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D003348:Cortisone / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007031:Hypothalamus / Q000503:physiopathology*; D007375:Interleukin-1 / Q000502:physiology; D053583:Interleukin-1beta; D008066:Lipolysis / Q000502:physiology; D009765:Obesity / Q000378:metabolism*; D010446:Peptide Fragments / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D007375:Interleukin-1; D053583:Interleukin-1beta; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C052994:interleukin-1beta (163-171); D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D003348:Cortisone; D006854:Hydrocortisone