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Context: Genetic variants affecting the nuclear hormone receptor coactivator steroid receptor coactivator, SRC-1, have been identified in people with severe obesity and impair melanocortin signaling in cells and mice. As a result, obese patients with SRC-1 deficiency are being treated with a melanocortin 4 receptor agonist in clinical trials., Objective: Here, our aim was to comprehensively describe and characterize the clinical phenotype of SRC-1 variant carriers to facilitate diagnosis and clinical management., Methods: In genetic studies of 2462 people with severe obesity, we identified 23 rare heterozygous variants in SRC-1. We studied 29 adults and 18 children who were SRC-1 variant carriers and performed measurements of metabolic and endocrine function, liver imaging, and adipose tissue biopsies. Findings in adult SRC-1 variant carriers were compared to 30 age- and body mass index (BMI)-matched controls., Results: The clinical spectrum of SRC-1 variant carriers included increased food intake in children, normal basal metabolic rate, multiple fractures with minimal trauma (40%), persistent diarrhea, partial thyroid hormone resistance, and menorrhagia. Compared to age-, sex-, and BMI-matched controls, adult SRC-1 variant carriers had more severe adipose tissue fibrosis (46.2% vs 7.1% respectively, P = .03) and a suggestion of increased liver fibrosis (5/13 cases vs 2/13 in controls, odds ratio = 3.4), although this was not statistically significant., Conclusion: SRC-1 variant carriers exhibit hyperphagia in childhood, severe obesity, and clinical features of partial hormone resistance. The presence of adipose tissue fibrosis and hepatic fibrosis in young patients suggests that close monitoring for the early development of obesity-associated metabolic complications is warranted., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Glucocorticoids (GCs) are commonly prescribed, but their use is associated with adverse metabolic effects. 5α-reductase inhibitors (5α-RI) are also frequently prescribed, mainly to inhibit testosterone conversion to dihydrotestosterone. However, they also prevent the inactivation of GCs., Objective: We hypothesized that 5α-RI may worsen the adverse effects of GCs., Design: Prospective, randomized study., Patients: A total of 19 healthy male volunteers (age 45 ± 2 years; body mass index 27.1 ± 0.7kg/m2)., Interventions: Participants underwent metabolic assessments; 2-step hyperinsulinemic, euglycemic clamp incorporating stable isotopes, adipose tissue microdialysis, and biopsy. Participants were then randomized to either prednisolone (10 mg daily) or prednisolone (10 mg daily) plus a 5α-RI (finasteride 5 mg daily or dutasteride 0.5 mg daily) for 7 days; metabolic assessments were then repeated., Main Outcome Measures: Ra glucose, glucose utilization (M-value), glucose oxidation, and nonesterified fatty acids (NEFA) levels., Results: Co-administration of prednisolone with a 5α-RI increased circulating prednisolone levels (482 ± 96 vs 761 ± 57 nmol/L, P = 0.029). Prednisolone alone did not alter Ra glucose (2.55 ± 0.34 vs 2.62 ± 0.19 mg/kg/minute, P = 0.86), M-value (3.2 ± 0.5 vs 2.7 ± 0.7 mg/kg/minute, P = 0.37), or glucose oxidation (0.042 ± 0.007 vs 0.040 ± 0.004 mmol/hr/kg/minute, P = 0.79). However, co-administration with a 5α-RI increased Ra glucose (2.67 ± 0.16 vs 3.05 ± 0.18 mg/kg/minute, P < 0.05) and decreased M-value (4.0 ± 0.5 vs 2.6 ± 0.4 mg/kg/minute, P < 0.05), and oxidation (0.043 ± 0.003 vs 0.036 ± 0.002 mmol/hr/kg, P < 0.01). Similarly, prednisolone did not impair insulin-mediated suppression of circulating NEFA (43.1 ± 28.9 vs 36.8 ± 14.3 μmol/L, P = 0.81), unless co-administered with a 5α-RI (49.8 ± 8.6 vs 88.5 ± 13.5 μmol/L, P < 0.01)., Conclusions: We have demonstrated that 5α-RIs exacerbate the adverse effects of prednisolone. This study has significant translational implications, including the need to consider GC dose adjustments, but also the necessity for increased vigilance for the development of adverse effects., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B-/-), the enzyme that converts fructose-1-phosphate to triose phosphates., Objective: To translate these experimental findings to the human situation., Design: Case-control study., Setting: Outpatient clinic for inborn errors of metabolism., Patients or Other Participants: Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15)., Main Outcome Measure: IHTG content, assessed by proton magnetic resonance spectroscopy., Results: IHTG content was higher in aldo B-/- patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m2, respectively). Glucose excursions during an oral glucose load were higher in aldo B-/- patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B-/- patients than in controls (P < 0.001). Finally, plasma β-hydroxybutyrate, a biomarker of hepatic β-oxidation, was lower in aldo B-/- patients than controls (P = 0.009)., Conclusions: This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of β-oxidation are involved in the pathogenesis., (Copyright © 2019 Endocrine Society.)

Context: The effects of energy-balanced bed rest on metabolic flexibility have not been thoroughly examined., Objective: We investigated the effects of 21 days of bed rest, with and without whey protein supplementation, on metabolic flexibility while maintaining energy balance. We hypothesized that protein supplementation mitigates metabolic inflexibility by preventing muscle atrophy., Design and Setting: Randomized crossover longitudinal study conducted at the German Aerospace Center, Cologne, Germany., Participants and Interventions: Ten healthy men were randomly assigned to dietary countermeasure or isocaloric control diet during a 21-day bed rest., Outcome Measures: Before and at the end of the bed rest, metabolic flexibility was assessed during a meal test. Secondary outcomes were glucose tolerance by oral glucose tolerance test, body composition by dual energy X-ray absorptiometry, ectopic fat storage by magnetic resonance imaging, and inflammation and oxidative stress markers., Results: Bed rest decreased the ability to switch from fat to carbohydrate oxidation when transitioning from fasted to fed states (i.e., metabolic inflexibility), antioxidant capacity, fat-free mass (FFM), and muscle insulin sensitivity along with greater fat deposition in muscle (P < 0.05 for all). Changes in fasting insulin and inflammation were not observed. However, glucose tolerance was reduced during acute overfeeding. Protein supplementation did not prevent FFM loss and metabolic alterations., Conclusions: Physical inactivity triggers metabolic inflexibility, even when energy balance is maintained. Although reduced insulin sensitivity and increased fat deposition were observed at the muscle level, systemic glucose intolerance was detected only in response to a moderately high-fat meal. This finding supports the role of physical inactivity in metabolic inflexibility and suggests that metabolic inflexibility precedes systemic glucose intolerance.

Context and Objectives: Spillover of fatty acids (FAs) into the plasma nonesterified fatty acid (NEFA) pool, because of an inability of adipose tissue (AT) to accommodate sufficient fat uptake, has been suggested to contribute to obesity-related insulin resistance. Using specific labeling techniques, we compared the proportion of spillover-derived NEFA across a range of adiposity., Participants and Methods: Seventy-one healthy men and women were fed a mixed meal (40 g fat) containing [U13C]palmitate to assess the contribution of chylomicron-derived spillover FAs. To investigate subcutaneous abdominal-specific spillover, arteriovenous difference and stable-isotope methodologies were used in substudy (six men, six women)., Results: Chylomicron-derived FA spillover was higher in individuals with a BMI <25 kg/m2 (n = 18) compared with those with a BMI ≥25 kg/m2 (n = 53) (22.2 ± 1.6% vs 18.6 ± 0.7%, P = 0.02). Women had higher chylomicron-derived FA spillover than age- and BMI-matched men (21.9 ± 1.1% vs 15.0 ± 1.6%, P = 0.001). Assessing spillover across subcutaneous abdominal AT showed higher proportions in women than in men (28.5 ± 6.1% vs 9.9 ± 1.3%, P = 0.01)., Conclusion: There is a considerable degree of spillover FA into the systemic NEFA pool in the postprandial state; this process is greater and more dynamic in lean individuals and women. Contrary to general perception, spillover of chylomicron-derived FA into systemic circulation is a physiologically normal feature most easily observed in people with a higher capacity for clearance of plasma triglycerides, but does not appear to be a pathway providing excess NEFA in obesity., (Copyright © 2017 Endocrine Society)

Context: 5α-Reductase 1 and 2 (SRD5A1, SRD5A2) inactivate cortisol to 5α-dihydrocortisol in addition to their role in the generation of DHT. Dutasteride (dual SRD5A1 and SRD5A2 inhibitor) and finasteride (selective SRD5A2 inhibitor) are commonly prescribed, but their potential metabolic effects have only recently been identified., Objective: Our objective was to provide a detailed assessment of the metabolic effects of SRD5A inhibition and in particular the impact on hepatic lipid metabolism., Design: We conducted a randomized study in 12 healthy male volunteers with detailed metabolic phenotyping performed before and after a 3-week treatment with finasteride (5 mg od) or dutasteride (0.5 mg od). Hepatic magnetic resonance spectroscopy (MRS) and two-step hyperinsulinemic euglycemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis were used to evaluate carbohydrate and lipid flux. Analysis of the serum metabolome was performed using ultra-HPLC-mass spectrometry., Setting: The study was performed in the Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, United Kingdom., Main Outcome Measure: Incorporation of hepatic lipid was measured with MRS., Results: Dutasteride, not finasteride, increased hepatic insulin resistance. Intrahepatic lipid increased on MRS after dutasteride treatment and was associated with increased rates of de novo lipogenesis. Adipose tissue lipid mobilization was decreased by dutasteride. Analysis of the serum metabolome demonstrated that in the fasted state, dutasteride had a significant effect on lipid metabolism., Conclusions: Dual-SRD5A inhibition with dutasteride is associated with increased intrahepatic lipid accumulation.

Context: Absence or excess of adipose tissue are both associated with metabolic complications, implying the importance of well-functioning adipose tissue present in normal amounts. Adipose tissue sequesters dietary fat and thus protects other tissues from excess fat exposure, especially after meals., Objective: The objective of the study was the use of an integrative physiological technique to quantify trafficking of fatty acids (FAs) in adipose tissue over a 24 h period., Methods: Adipose tissue FA handling was studied in response to three meals in eight healthy men by the combination of arteriovenous blood sampling, tissue blood flow, and specific labeling of FA tracing of exogenous and endogenous fat by stable isotope methodology., Results: The efficiency of adipose tissue FA uptake increased robustly with each meal. Chylomicron-triglyceride was the dominating source of FA. Adipose tissue fractional extraction of chylomicron-triglyceride increased from 21 +/- 4 to 47 +/- 8% (P = 0.03) between the first and last meal. Although adipose tissue lipoprotein lipase action increased with time (2-fold), there was an even greater increase in FA reesterification (3-fold), which led to a reduced spillover of chylomicron-derived FA, from 77 +/- 15 to 34 +/- 7% (P = 0.04) comparing the end of the first and the third meal period. Increased uptake of very low-density lipoprotein-derived FA was observed, but spillover of very low-density lipoprotein-derived FA was seen only in the fasting state., Conclusion: Human adipose tissue has a significant potential to up-regulate fat storage during a normal day that goes beyond increased lipoprotein lipase activation. The adaptation toward increasing fat storage may provide an explanation for the beneficial properties of normal amounts of adipose tissue.

Context: PPARG mutations may cause insulin resistance and dyslipidemia, but little is known about the mechanisms of the abnormalities of lipid metabolism., Objective: We hypothesized that in PPARG mutations, abnormal adipose tissue triglyceride storage causes insulin resistance., Design, Patients, and Main Outcome Measures: Whole-body and adipose tissue-specific metabolic phenotyping through arteriovenous blood sampling was made before and after a mixed meal including 13C-palmitic acid. Studies were performed in a 32-yr-old male with partial lipodystrophy and type 2 diabetes, heterozygous for the PPARG P467L mutation and in an apparently phenotypically normal 32-yr-old male heterozygous for the PPARG n.AAA553T mutation. Comparator groups were age- and sex-matched healthy participants (n=10) and type 2 diabetes sex-matched participants (n=6)., Results: The P467L patient had elevated unmodulated fasting and postprandial plasma nonesterified fatty acid (NEFA) concentrations, despite a low adipose tissue NEFA output. Instead, NEFA appeared to originate directly from triglyceride-rich lipoproteins: 13C-palmitic acid accumulated rapidly in the NEFA fraction, as a sign of impaired fatty acid trapping in tissues. In contrast to the Pparg haploinsufficient mouse, the patient with n.AAA553T mutation did not exhibit paradoxically insulin sensitive and showed a mostly normal metabolic pattern., Conclusions: The lipodystrophic PPARG P467L phenotype include excessive and uncontrolled generation of NEFA directly from triglyceride-rich lipoproteins, explaining high systemic NEFA concentrations, whereas the human PPARG haploinsufficiency is metabolically almost normal.