Liver is the site of splanchnic cortisol production in obese nondiabetic humans

OBJECTIVE—To determine the contribution of liver and viscera to splanchnic cortisol production in humans.RESEARCH DESIGN AND METHODS—D4 cortisol was infused intravenously; arterial, portal venous, and hepatic venous blood was sampled; and liver and visceral fat were biopsied in subjects undergoing bariatric surgery.RESULTS—Ratios of arterial and portal vein D4 cortisol/cortisol_total (0.06 ± 0.01 vs. 0.06 ± 0.01) and D4 cortisol/D3 cortisol (1.80 ± 0.14 vs. 1.84 ± 0.14) did not differ, indicating that no visceral cortisol production or conversion of D4 cortisol to D3 cortisol via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) occurred. Conversely, ratios of both D4 cortisol to cortisol_total (0.05 ± 0.01; P < 0.05) and D4 cortisol to D3 cortisol (1.33 ± 0.11; P < 0.001) were lower in the hepatic vein than in the portal vein, indicating production of both cortisol and D3 cortisol by the liver. The viscera did not produce either cortisol (−8.1 ± 2.6 μg/min) or D3 cortisol (−0.2 ± 0.1 μg/min). In contrast, the liver produced both cortisol (22.7 ± 3.90 μg/min) and D3 cortisol (1.9 ± 0.4 μg/min) and accounted for all splanchnic cortisol and D3 cortisol production. Additionally, 11β-HSD-1 mRNA was approximately ninefold higher (P < 0.01) in liver than in visceral fat. Although 11β-HSD-2 gene expression was very low in visceral fat, the viscera released cortisone (P < 0.001) and D3 cortisone (P < 0.01) into the portal vein.CONCLUSIONS—The liver accounts for all splanchnic cortisol production in obese nondiabetic humans. In contrast, the viscera releases cortisone into the portal vein, thereby providing substrate for intrahepatic cortisol production.Although it has been long known that glucocorticoids are potent regulators of glucose, fat, and protein metabolism, glucocorticoids have not been thought to cause insulin resistance in either obese or diabetic individuals because plasma concentrations do not differ from those present in lean nondiabetic subjects. However, extra-adrenal conversion of cortisone to cortisol via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) can result in high local concentrations of cortisol. This observation focused attention on the possibility that tissue-specific synthesis of glucocorticoids may contribute to the pathogenesis of insulin resistance and other components of the so called “metabolic syndrome” (1). The enzyme 11β-HSD-2 (which converts cortisol to cortisone) is present primarily in the kidney, whereas 11β-HSD-1 (which converts cortisone to cortisol) is present in both liver and adipose tissue with in vitro activity being greater in omental than subcutaneous fat deposits (2–5). Inhibition (6) or knockout (7–9) of 11β-HSD-1 in mice improves hepatic insulin action and protects against obesity and hyperglycemia. Conversely, selective overexpression of 11β-HSD-1 in adipose tissue in mice results in development of visceral obesity, hyperglycemia, hyperlipidemia, and hypertension (7–11).Using a novel tracer infusion method, Andrew et al. (12) demonstrated that infusion of [9,11,12,12-²H₄] cortisol (D4 cortisol) in fasting, nondiabetic humans resulted in the formation of measurable amounts of plasma [9,12,12-²H₃] cortisol (D3 cortisol). Because conversion of D4 cortisol to D3 cortisone by 11β-HSD-2 results in the loss of the 11 α-deuterium and the generation of D3 cortisone that in turn forms D3 cortisol when D3 cortisone is converted back to cortisol, this observation provides strong experimental evidence that the conversion of cortisone to cortisol occurs in humans (12). More recently, we used the same method in combination with the hepatic venous and leg catheterization techniques to determine the site(s) of conversion of cortisone to cortisol. Those studies (13) led to the discovery that rates of splanchnic cortisol production in healthy nondiabetic individuals equaled or even exceeded those produced by extrasplanchnic tissues (e.g., the adrenals). However, because concomitant uptake of cortisol also occurred within the splanchnic bed, only a small net amount of cortisol was released into the systemic circulation.Because portal venous blood was not sampled in those studies, we could not determine the individual contributions of the viscera and the liver to splanchnic cortisol production. We therefore addressed this question in a chronically catheterized conscious dog model that permitted simultaneous selective sampling of blood from an artery, the portal vein, and the hepatic vein during intravenous infusion of D4 cortisol (14). Surprisingly, we showed that the liver accounted for all of the splanchnic cortisol production in the dog without discernable release by the viscera. However, the dogs were lean, and it is unknown if the pattern of splanchnic cortisol production in dogs reflects that in humans. Therefore, it remained possible that visceral fat releases cortisol into the portal vein in obese humans, thereby exposing the liver to high local glucocorticoid concentrations.The present experiments addressed this question by selectively obtaining simultaneous samples of arterial, portal venous, and hepatic venous blood during a D4 cortisol infusion in severely obese subjects undergoing bariatric surgery. In addition, mRNA for the glucocorticoid receptor (NR3C1), 11β-HSD-1, and 11β-HSD-2 was measured in liver and visceral fat obtained during surgery. We report that the liver accounts for all of the splanchnic cortisol production in obese nondiabetic humans. In contrast, there was no detectible release of cortisol into the portal vein by the viscera. On the other hand, although the mRNA for 11β-HSD-2 in visceral fat was very low, the viscera released cortisone into the portal vein, thereby providing the liver with substrate for intrahepatic cortisol production.