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Metabolic effects of TNF-a depend on intact pituitary function
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With infusion of tumor necrosis factor-alpha, healthy men had greater increases in urea and amino acid fluxes and endogenous glucose production than men with hypopituitarism, according to research published in The Journal of Clinical Endocrinology & Metabolism.
The findings suggest that increases in endogenous cortisol and growth hormone release are significant components of the metabolic response to the proinflammatory cytokine tumor necrosis factor-alpha (TNF-a), according to researchers.
“Our data confirm that TNF-a induces increased lipolysis and increased amino acid/protein fluxes in healthy volunteers,” the researchers wrote. “In hypopituitary patients, there was no increase in lipolysis, no increase in urea fluxes and less pronounced increases in phenylalanine fluxes, suggesting that these metabolic processes depend on intact pituitary function and subsequent pituitary driven GH and cortisol secretion.”
Ermina Bach, MD, PhD, of Aarhus University, Denmark, and colleagues conducted a randomized, placebo-controlled, single blind trial to assess the differential effects of TNF-a on glucose, protein and lipid metabolism in eight hypopituitary patients without an intact hypothalamo-pituitary axis and eight healthy controls.
The investigators evaluated the men (mean age, 57 years) on two occasions — during TNF-a (12 ng/kg/hour) infusion and during placebo (isotonic saline) infusion. Effects were measured twice during 4-hour basal and 2-hour hyperinsulinemic clamp conditions with isotope dilution during 6 hours of infusion.
The researchers were primarily interested in the effects on phenylalanine, urea, palmitate and glucose fluxes and fat biopsies in basal and clamp periods.
TNF-a infusion significantly increased cortisol and GH levels in the control group, but not in the hypopituitary group. Although TNF-a increased phenylalanine fluxes in both groups, the increase was significantly higher in the control group; further, urea flux increased by 40% in the control group vs. no change in hypopituitary patients. Endogenous glucose production also was higher in the control group vs. the hypopituitary group after TNF-a infusion; insulin sensitivity was similarly unaffected in both groups.
Whole-body palmitate fluxes increased and palmitate specific activity decreased in the control group, but not in hypopituitary group with TNF-a administration; however, no statistical difference was seen between groups. No significant effects were detected with TNF-a on lipase expression or regulation in fat.
“Our results thus demonstrate that protein loss, ureagenesis and increased endogenous glucose production induced by TNF-a is critically dependent on intact pituitary function and suggest that the pituitary stress hormone response also contributes to the lipolytic effects of TNF-a,” the researchers wrote.
Disclosure: This work was supported by the Lundbeck Foundation, Denmark.
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