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BACKGROUND. Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant. METHODS. Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with metreleptin (n = 8) were continued on metreleptin for 5 days and then taken off metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naive patients (n = 14), who were reevaluated after 6 months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy. RESULTS. With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover). CONCLUSION. Using lipodystrophy as a human model of leptin deficiency and replacement, we show that metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake. TRIAL REGISTRATION. ClinicalTrials.gov NCT01778556 FUNDING. This research was supported by the intramural research program of the NIDDK., Introduction Leptin is an adipocyte-derived hormone that signals overall body energy sufficiency (1) and acute energy balance (2). Leptin-deficient states, such as starvation or mutations in the leptin gene, lead [...]

Background: People living with HIV have an increased risk of cardiovascular disease (CVD). Although coronary endothelial function (CEF) is an early direct indicator of CVD, only a few studies have been able to interrogate CEF directly. Most studies have examined vascular endothelial function through indirect assessment of brachial flow‐mediated dilatation (FMD). However, peripheral arteries are significantly larger and manifest atherogenesis differently from the coronary arteries, and so produce conflicting results. Additionally, none of these studies focused on young adults who acquired HIV perinatally or in early childhood. Objective: The present study investigates CEF in a unique population of young adults with lifelong HIV using direct magnetic resonance imaging (MRI) of coronary FMD (corFMD) with an in‐house developed MRI‐integrated isometric handgrip exercise system with continuous feedback and monitoring mechanisms (fmIHE). Methods: Young adults who acquired HIV perinatally or in early childhood (n = 23) and group‐matched healthy participants (n = 12) completed corFMD‐MRI with fmIHE. CorFMD was measured as the coronary cross‐sectional area response to the fmIHE. Results: In univariable and multivariable regression analysis, HIV status was a significant risk modifier. CD8+ T‐cell count and smoking pack‐years and their interaction with HIV status were independently associated with impaired coronary artery response to fmIHE. In people living with HIV, corFMD was significantly inversely correlated with CD8+ T‐cells and smoking pack‐years. In a multivariable regression analysis adjusted for age and body mass index, CD8+ T‐cells and smoking and their interaction with HIV status remained significant independent predictors of coronary endothelial dysfunction. Discussion: In this unique population of young adults, HIV status was a significant risk modifier, and immune activation and smoking were associated with decreased CEF, directly measured from the coronary vascular response to fmIHE. Conclusions: Management of CVD risk factors such as smoking and developing strategies that target immune activation in people living with HIV are warranted. [ABSTRACT FROM AUTHOR]

After myocardial infarction, ventricular geometry and function, as well as energy metabolism, change markedly. In nonischemic heart failure, inhibition of xanthine oxidase (XO) improves mechanoenergetic coupling by improving contractile performance relative to a reduced energetic demand. However, the metabolic and contractile effects of XO inhibitors (XOIs) have not been characterized in failing hearts after infarction. After undergoing permanent coronary ligation, mice received a XOI (allopurinol or oxypurinol) or matching placebo in the daily drinking water. Four weeks later, [sup.1]H MRI and [.sup.31]P magnetic resonance spectroscopy (MRS) were used to quantify in vivo functional and metabolic changes in postinfarction remodeled mouse myocardium and the effects of XOIs on that process. End-systolic (ESV) and end-diastolic volumes (EDV) were increased by more than sixfold after infarction, left ventricle (LV) mass doubled (P < 0.005), and the LV ejection fraction (EF) decreased (14 [+ or -] 9%) compared with control hearts (59 [+ or -] 8%, P < 0.005) at 1 mo. The myocardial phosphocreatine (PCr)-to-ATP ratio (PCr/ATP) was also significantly decreased in infarct remodeled hearts (1.4 [+ or -] 0.6) compared with control animals (2.1 [+ or -] 0.5, P < 0.02), in agreement with prior studies in larger animals. The XOIs allopurinol and oxypurinol did not change LV mass but limited the increase in ESV and EDV of infarct hearts by 50%, increased EF (23 [+ or -] 9%, P = 0.01), and normalized cardiac PCr/ATP (2.0 [+ or -] 0.5, P < 0.04). We conclude that XOIs improve ventricular function after infarction and normalize high-energy phosphate ratio in heart failure. Thus XOI therapy offers a new and potentially complementary approach to limit the adverse contractile and metabolic consequences after infarction. postinfarction remodeled myocardium; cardiac metabolism; magnetic resonance spectroscopy; allopurinol

Extended intracellular acidosis is evident in the brain after subarachnoid hemorrhage as indicated by phosphorus-31 magnetic resonance spectra. Potentially reversible ischemia is probably evident in the region of acidosis. Ischemia which may proceed to an irreversible neurological deficit may induce complication for subarachnoid hemorrhage.