Intact pituitary function is decisive for the catabolic response to TNF-α: studies of protein, glucose and fatty acid metabolism in hypopituitary and healthy subjects.
BACKGROUND
TNF-α generates inflammatory responses and insulin resistance, lipolysis, and protein breakdown. It is unclear whether these changes depend on intact hypothalamo-pituitary stress hormone responses to trigger the release of cortisol and growth hormone.


OBJECTIVE
To define differential effects of TNF-α on glucose, protein, and lipid metabolism in hypopituitary patients (without intact hypothalamo-pituitary axis) and healthy controls.


METHODS
Randomized, placebo controlled, single-blinded. Setting, Participants, and Intervention: We studied eight hypopituitary (HP) patients and eight matched control subjects [control volunteers (CTR)] twice during 4-h basal and 2-h hyperinsulinemic clamp conditions with isotope dilution during infusion of saline or TNF-α(12 ng/kg/h) for 6 h.


METHODS
Phenylalanine, urea, palmitate, and glucose fluxes and fat biopsies in basal and clamp periods.


RESULTS
TNF-α infusion significantly increased cortisol and GH levels in CTR but not in HP. TNF-α increased phenylalanine fluxes in both groups, with the increase being significantly greater in CTR, and raised urea flux by 40 % in CTR without any alteration in HP. Endogenous glucose production (EGP) was elevated in CTR compared to HP after TNF-α administration, whereas insulin sensitivity remained similarly unaffected in both groups. TNF-α increased whole body palmitate fluxes and decreased palmitate specific activity in CTR, but not in HP without statistical difference between groups. We did not detect significant effects TNF-α on lipase expression or regulation in fat.


CONCLUSIONS
TNF-α increased both urea and amino acid fluxes and EGP significantly more in CTR compared to HP, suggesting that increases in endogenous cortisol and GH release are significant components of the metabolic response to TNF-α.
Medical Research Laboratories (E.B., A.B.M., J.O.L.J., M.H.V., N.J., J.F.O., S.B.P., N.M.), Clinical Institute, Aarhus University, 8000 Aarhus, Denmark; Department of Endocrinology and Internal Medicine (E.B., A.B.M., J.O.L.J., M.H.V., N.J., J.F.O., S.B.P., N.M.), Aarhus University Hospital, 8000 Aarhus, Denmark; Department of Internal Medicine (E.B.), Viborg Regional Hospital, 8800 Viborg, Denmark; and The Novo Nordisk Foundation Centre for Basic Metabolic Research (T.S.N.), Section on Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
Ermina
E
Bach
Andreas B
AB
Møller
Jens O L
JO
Jørgensen
Mikkel H
MH
Vendelbo
Niels
N
Jessen
Jonas F
JF
Olesen
Steen B
SB
Pedersen
Thomas S
TS
Nielsen
Niels
N
Møller
D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism*; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007018:Hypopituitarism / Q000378:metabolism*; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D016037:Single-Blind Method; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014508:Urea / Q000378:metabolism
D005227:Fatty Acids; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D019382:Human Growth Hormone; D014508:Urea; D005947:Glucose; D006854:Hydrocortisone