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

TY - JOUR

T1 - Intact Pituitary Function is Decisive for the Catabolic Response to TNF-α

T2 - Studies of Protein, Glucose and Fatty Acid Metabolism in Hypopituitary and Healthy Subjects

AU - Bach, Ermina

AU - Møller, Andreas B

AU - Jørgensen, Jens O L

AU - Vendelbo, Mikkel H

AU - Jessen, Niels

AU - Olesen, Jonas F

AU - Pedersen, Steen B

AU - Nielsen, Thomas Svava

AU - Møller, Niels

PY - 2015/2/1

Y1 - 2015/2/1

N2 - Context: 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. Design: 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. Main Outcome Measures: 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.

AB - Context: 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. Design: 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. Main Outcome Measures: 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.

U2 - 10.1210/jc.2014-2489

DO - 10.1210/jc.2014-2489

M3 - Journal article

C2 - 25375979

SN - 0021-972X

VL - 100

SP - 578

EP - 586

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 2

ER -