CDK4-E2F3 signals enhance oxidative skeletal muscle fiber numbers and function to affect myogenesis and metabolism.

Understanding how skeletal muscle fiber proportions are regulated is vital to understanding muscle function. Oxidative and glycolytic skeletal muscle fibers differ in their contractile ability, mitochondrial activity, and metabolic properties. Fiber-type proportions vary in normal physiology and disease states, although the underlying mechanisms are unclear. In human skeletal muscle, we observed that markers of oxidative fibers and mitochondria correlated positively with expression levels of PPARGC1A and CDK4 and negatively with expression levels of CDKN2A, a locus significantly associated with type 2 diabetes. Mice expressing a constitutively active Cdk4 that cannot bind its inhibitor p16INK4a, a product of the CDKN2A locus, were protected from obesity and diabetes. Their muscles exhibited increased oxidative fibers, improved mitochondrial properties, and enhanced glucose uptake. In contrast, loss of Cdk4 or skeletal muscle-specific deletion of Cdk4's target, E2F3, depleted oxidative myofibers, deteriorated mitochondrial function, and reduced exercise capacity, while increasing diabetes susceptibility. E2F3 activated the mitochondrial sensor PPARGC1A in a Cdk4-dependent manner. CDK4, E2F3, and PPARGC1A levels correlated positively with exercise and fitness and negatively with adiposity, insulin resistance, and lipid accumulation in human and rodent muscle. All together, these findings provide mechanistic insight into regulation of skeletal muscle fiber-specification that is of relevance to metabolic and muscular diseases.

Prevalence of Hypothyroidism in Patients With Erdheim-Chester Disease.

Importance: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis affecting multiple organs and commonly caused by somatic pathogenic variants in BRAF V600E and mitogen-activated protein kinase genes. Clinical features of ECD result from histiocytic involvement of various tissues; while endocrine involvement in ECD occurs frequently, the prevalence of central or primary hypothyroidism has not been thoroughly investigated. Objective: To assess hypothalamus-pituitary-thyroid (HPT) dysfunction in patients with ECD. Design, Setting, and Participants: This cross-sectional study included 61 patients with ECD who were enrolled in a natural history study at a tertiary care center between January 2011 and December 2018. ECD was diagnosed on the basis of clinical, genetic, and histopathological features. Data were analyzed in March 2020. Exposure: Diagnosis of ECD. Main Outcomes and Measures: Main outcome was the prevalence of thyroid dysfunction in adults with ECD compared with community estimates. Patients underwent baseline evaluation with a thyroid function test, including thyrotropin, free thyroxine (fT4), and total thyroxine (T4), and sellar imaging with magnetic resonance imaging or computed tomography scan. The association of HPT dysfunction was assessed for differences in age, sex, body mass index, BRAF V600E status, high sensitivity C-reactive protein level, sellar imaging, and pituitary hormonal dysfunction. Results: A total of 61 patients with ECD (46 [75%] men; mean [SD] age, 54.3 [10.9] years) were evaluated. Seventeen patients (28%) had hypothyroidism requiring levothyroxine therapy. The prevalence of both central and primary hypothyroidism were higher than community estimates (central hypothyroidism: 9.8% vs 0.1%; odds ratio, 109.0; 95% CI, 37.4-260.6; P < .001; primary hypothyroidism: 18.0% vs 4.7%; OR, 4.4; 95% CI, 2.1-8.7; P < .001). Patients with hypothyroidism (both primary and central), compared with patients with euthyroidism, had higher body mass index (median [interquartile range] 31.4 [28.3-38.3] vs 26.7 [24.4-31.9]; P = .004) and a higher prevalence of panhypopituitarism (7 [47%] vs 3 [7%]; P < .001). Among patients with hypothyroidism, those with central hypothyroidism, compared with patients with primary hypothyroidism, had a lower mean (SD) body mass index (28.3 [2.6] vs 36.3 [5.9]; P = .007) and higher frequencies of abnormal sellar imaging (5 [83%] vs 3 [27%]; P = .050) and panhypopituitarism (5 [83%] vs 3 [27%]; P = .050). Conclusions and Relevance: In this cohort study, a higher prevalence of central and primary hypothyroidism was identified in patients with ECD compared with the community. There should be a low threshold for testing for hypothyroidism in patients with ECD, and treatment should follow standard guidelines.

Adipocyte ß-arrestin-2 is essential for maintaining whole body glucose and energy homeostasis.

ß-Arrestins are major regulators of G protein-coupled receptor-mediated signaling processes. Their potential roles in regulating adipocyte function in vivo remain unexplored. Here we report the novel finding that mice lacking ß-arrestin-2 (barr2) selectively in adipocytes show significantly reduced adiposity and striking metabolic improvements when consuming excess calories. We demonstrate that these beneficial metabolic effects are due to enhanced signaling through adipocyte ß3-adrenergic receptors (ß3-ARs), indicating that barr2 represents a potent negative regulator of adipocyte ß3-AR activity in vivo. Interestingly, essentially all beneficial metabolic effects caused by adipocyte barr2 deficiency are absent in adipocyte barr2-PRDM16 double KO mice, indicating that the metabolic improvements caused by the lack of barr2 in adipocytes are mediated by the browning/beiging of white adipose tissue. Our data support the novel concept that 'G protein-biased' ß3-AR agonists that do not promote ß3-AR/barr2 interactions may prove useful for the treatment of obesity and related metabolic disorders.

Predictive Accuracy of Surrogate Indices for Hepatic and Skeletal Muscle Insulin Sensitivity.

CONTEXT: Surrogate indices of muscle and hepatic insulin sensitivity derived from an oral glucose tolerance test (OGTT) are frequently used in clinical studies. However, the predictive accuracy of these indices has not been validated. DESIGN: In this cross-sectional study, hyperinsulinemic-euglycemic glucose clamp with tritiated glucose infusion and a 75-g OGTT were performed in individuals (n = 659, aged 18 to 49 years, body mass index of 16 to 64 kg/m2) with varying degrees of glucose tolerance. A calibration model was used to assess the ability of OGTT-derived, tissue-specific surrogate indices [hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI)] to predict insulin sensitivity/resistance indices derived from the reference glucose clamp [Hepatic-IRbasal, a product of fasting plasma insulin and hepatic glucose production (HGP), Hepatic-IRclamp, reciprocal of the percent suppression of HGP during the insulin clamp corrected for plasma insulin concentration, and Muscle-ISclamp, a measure of peripheral glucose disposal]. Predictive accuracy was assessed by root mean squared error of prediction and leave-one-out, cross-validation-type square root of the mean squared error of prediction. RESULTS: HIRI and MISI were correlated with their respective clamp-derived indices. HIRI was negatively related to Muscle-ISclamp (r = -0.62, P < 0.0001) and MISI correlated with Hepatic-IR derived from the clamp (Hepatic-IRbasal: r = -0.48, P < 0.0001 and Hepatic-IRclamp: r = -0.41, P < 0.0001). However, the accuracy of HIRI and MISI to predict Hepatic-IR (basal or during clamp) was not significantly different. Likewise, the ability of HIRI and MISI to predict Muscle-ISclamp was also similar. CONCLUSION: Our findings indicate that the surrogate indices derived from an OGTT are accurate in predicting insulin sensitivity but are not tissue specific.

Increased Physical Activity Associated with Less Weight Regain Six Years After "The Biggest Loser" Competition.

OBJECTIVE: The aim of this study was to explore how physical activity (PA) and energy intake (EI) changes were related to weight loss and regain following "The Biggest Loser" competition. METHODS: At baseline, week 6 and week 30 of the competition, and 6 years after the competition, body composition was measured via dual-energy x-ray absorptiometry, resting energy expenditure was measured by using indirect calorimetry, and EI and PA were measured by using doubly labeled water. RESULTS: Six years after the competition, median weight loss in 14 of "The Biggest Loser" participants was 13%, with those maintaining a greater weight loss (mean ± SE) of 24.9% ± 3.8% having increased PA by 160% ± 23%, compared with a PA increase of 34% ± 25% (P = 0.0033) in the weight regainers who were 1.1% ± 4.0% heavier than the precompetition baseline. EI changes were similar between weight loss maintainers and regainers (-8.7% ± 5.6% vs. -7.4% ± 2.7%, respectively; P = 0.83). Weight regain was inversely associated with absolute changes in PA (r = -0.82; P = 0.0003) but not with changes in EI (r = -0.15; P = 0.61). EI and PA changes explained 93% of the individual weight loss variability at 6 years. CONCLUSIONS: Consistent with previous reports, large and persistent increases in PA may be required for long-term maintenance of lost weight.

Metreleptin therapy lowers plasma angiopoietin-like protein 3 in patients with generalized lipodystrophy.

BACKGROUND: Reduced triglyceride clearance due to impaired lipoprotein lipase-mediated lipolysis contributes to severe hypertriglyceridemia in lipodystrophy. Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) impair clearance of triglycerides by inhibiting lipoprotein lipase. Whether circulating ANGPTL3/4 levels are altered in lipodystrophy and the effects of leptin replacement on these ANGPTLs are unknown. OBJECTIVE: To examine if ANGPTL3/4 levels are elevated in patients with generalized lipodystrophy and assess the effects of leptin replacement on these ANGPTLs. METHODS: Preleptin treatment plasma levels of ANGPTLs in patients with generalized lipodystrophy (n = 22) were compared with healthy controls (n = 39) using a post hoc case-control study design. In a prospective open-label study, we studied the effects of metreleptin therapy (16-32 weeks) on plasma ANGPTL3/4 in patients with generalized lipodystrophy. RESULTS: Plasma ANGPTL3 (geometric mean [95% confidence interval]; 223 [182-275] vs 174 ng/mL [160-189], P = .02) but not ANGPTL4 levels (55 [37-81] vs 44 ng/mL [37-52], P = .26) were higher in patients with lipodystrophy compared with healthy controls. There was a significant decrease in total cholesterol, triglycerides, and glycosylated hemoglobin (A1C) levels following metreleptin therapy. After metreleptin, ANGPTL3 concentrations decreased significantly (223 [182-275] vs 175 ng/mL [144-214], P = .01) with no change in ANGPTL4 (55 [37-81] vs 48 ng/mL [32-73], P = .11). CONCLUSIONS: These findings suggest that elevated plasma levels of ANGPTL3 in leptin-deficient states is attenuated with leptin therapy.

Plasma serpinB1 is related to insulin sensitivity but not pancreatic ß-Cell function in non-diabetic adults.

Pancreatic ß-cell dysfunction because of reduced ß-cell mass and function is a primary determinant in the progression of diabetes. Increase in ß-cell mass and compensatory hyperinsulinaemia is frequently associated with insulin-resistant states. Although the humoral factors mediating this compensatory response are unknown, serpinB1, a protease inhibitor, has recently been proposed to be one such factor. In this study, we examine the relationships between plasma serpinB1, insulin sensitivity, and pancreatic ß-cell function in non-diabetic individuals. 117 subjects (women, n = 50, men, n = 67; age= 37.6 ± 10.8; BMI=31.1 ± 7.7 kg/m2) underwent an insulin-modified frequently sampled intravenous glucose tolerance test (FSIVGTT) at the NIH Clinical Research Center. Acute insulin response (AIR) and insulin sensitivity index (SI) were obtained from the FSIVGTT with MINMOD analysis. The Quantitative Insulin Sensitivity Check Index (QUICKI) was calculated from fasting insulin and glucose values. Plasma serpinB1 levels were measured using an ELISA assay. Simple linear correlation analyses were performed to evaluate the relationship between serpinB1 and measures of insulin sensitivity and ß-cell function. Circulating serpinB1 levels were unrelated to age, sex, race, BMI, or percent body fat. SI but not AIR significantly correlated with circulating serpinB1 levels (r = 0.23, P < 0.05). QUICKI tended to positively correlate with serpinB1 (r = 0.16, P = 0.09). Circulating serpinB1 is directly associated with insulin sensitivity but not ß-cell function in non-diabetic adults. Whether this modest association plays a role in insulin sensitivity in humans remains to be clarified.

Persistent metabolic adaptation 6 years after "The Biggest Loser" competition.

OBJECTIVE: To measure long-term changes in resting metabolic rate (RMR) and body composition in participants of "The Biggest Loser" competition. METHODS: Body composition was measured by dual energy X-ray absorptiometry, and RMR was determined by indirect calorimetry at baseline, at the end of the 30-week competition and 6 years later. Metabolic adaptation was defined as the residual RMR after adjusting for changes in body composition and age. RESULTS: Of the 16 "Biggest Loser" competitors originally investigated, 14 participated in this follow-up study. Weight loss at the end of the competition was (mean ± SD) 58.3 ± 24.9 kg (P < 0.0001), and RMR decreased by 610 ± 483 kcal/day (P = 0.0004). After 6 years, 41.0 ± 31.3 kg of the lost weight was regained (P = 0.0002), while RMR was 704 ± 427 kcal/day below baseline (P < 0.0001) and metabolic adaptation was -499 ± 207 kcal/day (P < 0.0001). Weight regain was not significantly correlated with metabolic adaptation at the competition's end (r = -0.1, P = 0.75), but those subjects maintaining greater weight loss at 6 years also experienced greater concurrent metabolic slowing (r = 0.59, P = 0.025). CONCLUSIONS: Metabolic adaptation persists over time and is likely a proportional, but incomplete, response to contemporaneous efforts to reduce body weight.

TSH/IGF-1 Receptor Cross Talk in Graves' Ophthalmopathy Pathogenesis.

CONTEXT: The TSH receptor (TSHR) is considered the main target of stimulatory autoantibodies in the pathogenesis of Graves' ophthalmopathy (GO); however, it has been suggested that stimulatory IGF-1 receptor (IGF-1R) autoantibodies also play a role. OBJECTIVE: We previously demonstrated that a monoclonal stimulatory TSHR antibody, M22, activates TSHR/IGF-1R cross talk in orbital fibroblasts/preadipocytes obtained from patients with GO (GO fibroblasts [GOFs]). We show that cross talk between TSHR and IGF-1R, not direct IGF-1R activation, is involved in the mediation of GO pathogenesis stimulated by Graves' autoantibodies. DESIGN/SETTING/PARTICIPANTS: Immunoglobulins were purified from the sera of 57 GO patients (GO-Igs) and tested for their ability to activate TSHR and/or IGF-1R directly and TSHR/IGF-1R cross talk in primary cultures of GOFs. Cells were treated with M22 or GO-Igs with or without IGF-1R inhibitory antibodies or linsitinib, an IGF-1R kinase inhibitor. MAIN OUTCOME MEASURES: Hyaluronan (hyaluronic acid [HA]) secretion was measured as a major biological response for GOF stimulation. IGF-1R autophosphorylation was used as a measure of direct IGF-1R activation. TSHR activation was determined through cAMP production. RESULTS: A total of 42 out of 57 GO-Ig samples stimulated HA secretion. None of the GO-Ig samples exhibited evidence for IGF-1R autophosphorylation. Both anti-IGF-1R antibodies completely inhibited IGF-1 stimulation of HA secretion. By contrast, only 1 IGF-1R antibody partially blocked HA secretion stimulated by M22 or GO-Igs in a manner similar to linsitinib, whereas the other IGF-1R antibody had no effect on M22 or GO-Ig stimulation. These findings show that the IGF-1R is involved in GO-Igs stimulation of HA secretion without direct activation of IGF-1R. CONCLUSIONS: IGF-1R activation by GO-Igs occurs via TSHR/IGF-1R cross talk rather than direct binding to IGF-1R, and this cross talk is important in the pathogenesis of GO.

Effect of Leptin Administration on Circulating Apolipoprotein CIII levels in Patients With Lipodystrophy.

CONTEXT: Apolipoprotein CIII (apoCIII), an inhibitor of lipoprotein lipase, plays an important role in triglyceride metabolism. However, the role of apoCIII in hypertriglyceridemia in lipodystrophy and the effects of leptin replacement on apoCIII levels are unknown. OBJECTIVE: The objective of the study was to test the hypotheses that apoCIII is elevated in hypertriglyceridemic patients with lipodystrophy and that leptin replacement in these patients lowers circulating apoCIII. DESIGN, SETTING, STUDY PARTICIPANTS, INTERVENTION, AND OUTCOME MEASURES: Using a post hoc cross-sectional case-control design, we compared serum apoCIII levels from patients with lipodystrophy not associated with HIV (n = 60) and age-, gender-, race-, and ethnicity-matched controls (n = 54) participating in ongoing studies at the National Institutes of Health. In a prospective, open-label, ongoing study, we studied the effects of 6­12 months of leptin replacement on apoCIII in lipodystrophy patients as an exploratory outcome. RESULTS: ApoCIII was higher in lipodystrophy patients (geometric mean [25th and 75th percentiles]) (23.9 mg/dL [14.6, 40.3]) compared with controls (14.9 mg/dL [12.3, 17.7]) (P < .0001). ApoCIII and triglyceride levels were positively correlated in patients with lipodystrophy (R = 0.72, P < .0001) and healthy controls (R = 0.6, P < .0001). Leptin replacement (6­12 mo) did not significantly alter apoCIII (before leptin: 23.4 mg/dL [14.5, 40.1]; after leptin: 21.4 mg/dL [16.7, 28.3]; P = .34). CONCLUSIONS: Leptin replacement in lipodystrophy did not alter serum apoCIII levels. Elevated apoCIII may play a role in the hypertriglyceridemia of lipodystrophy independent of leptin deficiency and replacement.

An improved micro-method for the measurement of steroid profiles by APPI-LC-MS/MS and its use in assessing diurnal effects on steroid concentrations and optimizing the diagnosis and treatment of adrenal insufficiency and CAH.

Our goals were to (1) develop an improved micro-method usable for neonates for steroid profile measurements and a method to measure androsterone, a key steroid in the recently described androgen backdoor pathway together, with dehydroepiandrosterone and (2) to assess if dehydroepiandrosterone diurnal concentration fluctuations exist potentially necessitating strict adherence to time of blood sample draw and requirement of separate time-dependent reference intervals. Liquid chromatography-tandem mass spectrometry was performed with an atmospheric pressure photoionization source [1]. For each sample 50µL (100µL for the backdoor pathway) of serum was deproteinized by adding 75µL (150µL for the backdoor pathway) of acetonitrile containing the internal standards. After centrifugation, 75µL (150µL for the backdoor pathway) of supernatant was diluted with 250µL of water and injected onto a Poroshell 120 EC-C8 column (SB-C8 column for the backdoor pathway). Within-run coefficients of variation ranged from 2.4 to 10.4% and between-day coefficients of variation from 2.9 to 11.2%. Comparison studies yielded correlation coefficient between 0.97 and 1.00 with recoveries of 90% or greater. Our methods analyze a 9 steroid profile and an additional 2 steroid profile (backdoor pathway) with minimal sample volume (usable in neonates optimizing early diagnosis of endocrinopathies and genetic diseases). Low limits of quantitation make these methods ideal for steroid measurement in women and prepubertal children. As diurnal variations of dehydroepiandrosterone and other steroids [2] concentrations are clinically significant we recommend that separate reference intervals be developed for 8 am, 8 pm, and midnight sample draws. The use of this approach in improving the diagnosis of patients with adrenal insufficiency and congenital adrenal hyperplasia is discussed.

Effects of Recombinant Human Leptin (Metreleptin) on Nocturnal Luteinizing Hormone Secretion in Lipodystrophy Patients.

BACKGROUND: Leptin replacement in patients with leptin gene mutations improves hypogonadotropic hypogonadism. The effects of leptin replacement on luteinizing hormone (LH) secretion in patients with lipodystrophy are unknown. AIM: We examined nocturnal LH secretory dynamics on and off exogenous leptin therapy using a 2-period, nonrandomized study that included leptin-naïve and leptin-treated subjects with lipodystrophy. METHODS: In period 1 (5 days) the leptin-treated group (n = 4) continued leptin; leptin was then withdrawn for the next 14 days (period 2). Leptin-naïve subjects (n = 8) were studied without leptin in period 1 and with leptin replacement in period 2. LH secretory dynamics were assessed (23:00-07:00 h, sampling every 10 min, analyzed by multiparameter deconvolution algorithm) at the end of each period. RESULTS: Mean (on vs. off: 5.0 ± 3.1 vs. 3.2 ± 1.3 IU/l, p = 0.04) and integrated LH concentrations (2,403 ± 1,495 vs. 1,534 ± 642 IU × l-1 × min-1, p = 0.04) were higher on leptin therapy. Leptin treatment increased burst mass (9.7± 15.4 vs. 7.0 ± 11.2 IU/l, p = 0.03) and tended to nonsignificantly increase LH burst frequency (0.77 ± 0.26 vs. 0.67 ± 0.24 h-1, p = 0.08). Consequently, leptin therapy increased the pulsatile production rate (64 ± 101 vs. 57 ± 73 IU × l-1 × 8 h-1, p = 0.01). On leptin, testosterone (507 ± 286 vs. 360 ± 174 ng/dl, p = 0.09) and estradiol levels (74 ± 36 vs. 29 ± 24 pg/ml, p = 0.01) were higher in males and females, respectively. CONCLUSIONS: Leptin increases spontaneous nocturnal LH secretion in patients with lipodystrophy. This is consistent with rodent and in vitro studies showing a direct stimulatory effect (hypothalamic, pituitary or both) of leptin on LH secretion. These novel findings may explicate some of the salutary effects of leptin therapy on the hypothalamic-pituitary-gonadal axis in lipodystrophy.

Calorie for Calorie, Dietary Fat Restriction Results in More Body Fat Loss than Carbohydrate Restriction in People with Obesity.

Dietary carbohydrate restriction has been purported to cause endocrine adaptations that promote body fat loss more than dietary fat restriction. We selectively restricted dietary carbohydrate versus fat for 6 days following a 5-day baseline diet in 19 adults with obesity confined to a metabolic ward where they exercised daily. Subjects received both isocaloric diets in random order during each of two inpatient stays. Body fat loss was calculated as the difference between daily fat intake and net fat oxidation measured while residing in a metabolic chamber. Whereas carbohydrate restriction led to sustained increases in fat oxidation and loss of 53 ± 6 g/day of body fat, fat oxidation was unchanged by fat restriction, leading to 89 ± 6 g/day of fat loss, and was significantly greater than carbohydrate restriction (p = 0.002). Mathematical model simulations agreed with these data, but predicted that the body acts to minimize body fat differences with prolonged isocaloric diets varying in carbohydrate and fat.

Reassessing the NTCTCS Staging Systems for Differentiated Thyroid Cancer, Including Age at Diagnosis.

BACKGROUND: Thyroid cancer is unique for having age as a staging variable. Recently, the commonly used age cut-point of 45 years has been questioned. OBJECTIVE: This study assessed alternate staging systems on the outcome of overall survival, and compared these with current National Thyroid Cancer Treatment Cooperative Study (NTCTCS) staging systems for papillary and follicular thyroid cancer. METHODS: A total of 4721 patients with differentiated thyroid cancer were assessed. Five potential alternate staging systems were generated at age cut-points in five-year increments from 35 to 70 years, and tested for model discrimination (Harrell's C-statistic) and calibration (R(2)). The best five models for papillary and follicular cancer were further tested with bootstrap resampling and significance testing for discrimination. RESULTS: The best five alternate papillary cancer systems had age cut-points of 45-50 years, with the highest scoring model using 50 years. No significant difference in C-statistic was found between the best alternate and current NTCTCS systems (p = 0.200). The best five alternate follicular cancer systems had age cut-points of 50-55 years, with the highest scoring model using 50 years. All five best alternate staging systems performed better compared with the current system (p = 0.003-0.035). There was no significant difference in discrimination between the best alternate system (cut-point age 50 years) and the best system of cut-point age 45 years (p = 0.197). CONCLUSIONS: No alternate papillary cancer systems assessed were significantly better than the current system. New alternate staging systems for follicular cancer appear to be better than the current NTCTCS system, although they require external validation.

Long-Term Outcomes Following Therapy in Differentiated Thyroid Carcinoma: NTCTCS Registry Analysis 1987-2012.

CONTEXT: Initial treatments for patients with differentiated thyroid cancer are supported primarily by single-institution, retrospective studies, with limited follow-up and low event rates. We report updated analyses of long-term outcomes after treatment in patients with differentiated thyroid cancer. OBJECTIVE: The objective was to examine effects of initial therapies on outcomes. DESIGN/SETTING: This was a prospective multi-institutional registry. PATIENTS: A total of 4941 patients, median follow-up, 6 years, participated. INTERVENTION: Interventions included total/near-total thyroidectomy (T/NTT), postoperative radioiodine (RAI), and thyroid hormone suppression therapy (THST). MAIN OUTCOME MEASURE: Main outcome measures were overall survival (OS) and disease-free survival using product limit and proportional hazards analyses. RESULTS: Improved OS was noted in NTCTCS stage III patients who received RAI (risk ratio [RR], 0.66; P = .04) and stage IV patients who received both T/NTT and RAI (RR, 0.66 and 0.70; combined P = .049). In all stages, moderate THST (TSH maintained subnormal-normal) was associated with significantly improved OS (RR stages I-IV: 0.13, 0.09, 0.13, 0.33) and disease-free survival (RR stages I-III: 0.52, 0.40, 0.18); no additional survival benefit was achieved with more aggressive THST (TSH maintained undetectable-subnormal). This remained true, even when distant metastatic disease was diagnosed during follow-up. Lower initial stage and moderate THST were independent predictors of improved OS during follow-up years 1-3. CONCLUSIONS: We confirm previous findings that T/NTT followed by RAI is associated with benefit in high-risk patients, but not in low-risk patients. In contrast with earlier reports, moderate THST is associated with better outcomes across all stages, and aggressive THST may not be warranted even in patients diagnosed with distant metastatic disease during follow-up. Moderate THST continued at least 3 years after diagnosis may be indicated in high-risk patients.

Myocardial Fat Accumulation Is Independent of Measures of Insulin Sensitivity.

BACKGROUND: Myocardial steatosis, an independent predictor of diastolic dysfunction, is frequently present in type 2 diabetes mellitus. High free fatty acid flux, hyperglycemia, and hyperinsulinemia may play a role in myocardial steatosis. There are no prior studies examining the relationship between insulin sensitivity (antilipolytic and glucose disposal actions of insulin) and cardiac steatosis. OBJECTIVE: Using a cross-sectional study design of individuals with and without metabolic syndrome (MetSyn), we examined the relationships between cardiac steatosis and the sensitivity of the antilipolytic and glucose disposal actions of insulin. METHODS: Pericardial fat (PF) volume, intramyocardial and hepatic fat (MF and HF) content, visceral fat (VF) and sc fat content were assessed by magnetic resonance imaging in 77 subjects (49 without MetSyn and 28 with MetSyn). In a subset of the larger cohort (n = 52), peripheral insulin sensitivity index (SI) and adipocyte insulin sensitivity (Adipo-SI) were determined from an insulin-modified frequently sampled iv glucose tolerance test. The Quantitative Insulin Sensitivity Check Index was used as a surrogate for hepatic insulin sensitivity. RESULTS: Individuals with the MetSyn had significantly higher body mass index, total body fat, and MF, PF, HF, and VF content. HF and VF, but not MF, were negatively correlated with the Quantitative Insulin Sensitivity Check Index, Adipo-SI, and SI. Stepwise regression revealed that waist circumference and serum triglyceride levels independently predicted MF and PF, respectively. Adipo-SI and serum triglyceride levels independently predict HF. CONCLUSION: Myocardial steatosis is unrelated to hepatic, adipocyte, or peripheral insulin sensitivity. Although it is frequently observed in insulin-resistant subjects, further studies are necessary to identify and delineate pathogenic mechanisms that differentially affect cardiac and hepatic steatosis.

Does Visceral Fat Estimated by Dual-Energy X-ray Absorptiometry Independently Predict Cardiometabolic Risks in Adults?

BACKGROUND: Abdominal visceral fat, typically measured by computer tomography (CT) or magnetic resonance imaging (MRI), has been shown to correlate with cardiometabolic risks. The purpose of this study was to examine whether a newly developed and validated visceral fat measurement from dual-energy X-ray absorptiometry (DXA) provides added predictive value to the cross-sectional differences of cardiometabolic parameters beyond the traditional anthropometric and DXA adiposity parameters. METHOD: A heterogeneous cohort of 194 adults (81 males and 113 females) with a BMI of 19 to 54 kg/m(2) participated in this cross-sectional study. Body composition was measured with a DXA densitometer. Visceral fat was then computed with a proprietary algorithm. Insulin sensitivity index (SI, measured by intravenous glucose tolerance test), blood pressures, and lipid profiles, and peak oxygen uptake were also measured as cardiometabolic risk parameters. RESULTS: DXA-estimated visceral fat mass was associated with HDL cholesterol (regression coefficient [ß] = -5.15, P < .01, adjusted R(2) = .21), triglyceride (ß = 26.01, P < .01, adjusted R(2) = .14), and peak oxygen uptake (ß = -3.15, P < .01, adjusted R(2) = .57) after adjusting for age, gender, and ethnicity. A subanalysis stratifying gender-specific BMI tertiles showed visceral fat, together with ethnicity, was independently associated with SI in overweight men and moderately obese women (second tertile). CONCLUSIONS: Without requiring additional CT or MRI-based measurements, visceral fat detected by DXA might offer certain advantages over the traditional DXA adiposity parameters as means of assessing cardiometabolic risks.

Human adipose cells in vitro are either refractory or responsive to insulin, reflecting host metabolic state.

While intercellular communication processes are frequently characterized by switch-like transitions, the endocrine system, including the adipose tissue response to insulin, has been characterized by graded responses. Yet here individual cells from adipose tissue biopsies are best described by a switch-like transition between the basal and insulin-stimulated states for the trafficking of the glucose transporter GLUT4. Two statistically-defined populations best describe the observed cellular heterogeneity, representing the fractions of refractive and responsive adipose cells. Furthermore, subjects exhibiting high systemic insulin sensitivity indices (SI) have high fractions of responsive adipose cells in vitro, while subjects exhibiting decreasing SI have increasing fractions of refractory cells in vitro. Thus, a two-component model best describes the relationship between cellular refractory fraction and subject SI. Since isolated cells exhibit these different response characteristics in the presence of constant culture conditions and milieu, we suggest that a physiological switching mechanism at the adipose cellular level ultimately drives systemic SI.

RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals.

CONTEXT: Activation of the melanocortin-4 receptor (MC4R) with the synthetic agonist RM-493 decreases body weight and increases energy expenditure (EE) in nonhuman primates. The effects of MC4R agonists on EE in humans have not been examined to date. OBJECTIVE, DESIGN, AND SETTING: In a randomized, double-blind, placebo-controlled, crossover study, we examined the effects of the MC4R agonist RM-493 on resting energy expenditure (REE) in obese subjects in an inpatient setting. STUDY PARTICIPANTS AND METHODS: Twelve healthy adults (6 men and 6 women) with body mass index of 35.7 ± 2.9 kg/m(2) (mean ± SD) received RM-493 (1 mg/24 h) or placebo by continuous subcutaneous infusion over 72 hours, followed immediately by crossover to the alternate treatment. All subjects received a weight-maintenance diet (50% carbohydrate, 30% fat, and 20% protein) and performed 30 minutes of standardized exercise daily. Continuous EE was measured on the third treatment day in a room calorimeter, and REE in the fasting state was defined as the mean of 2 30-minute resting periods. RESULTS: RM-493 increased REE vs placebo by 6.4% (95% confidence interval, 0.68-13.02%), on average by 111 kcal/24 h (95% confidence interval, 15-207 kcal, P = .03). Total daily EE trended higher, whereas the thermic effect of a test meal and exercise EE did not differ significantly. The 23-hour nonexercise respiratory quotient was lower during RM-493 treatment (0.833 ± 0.021 vs 0.848 ± 0.022, P = .02). No adverse effect on heart rate or blood pressure was observed. CONCLUSIONS: Short-term administration of the MC4R agonist RM-493 increases REE and shifts substrate oxidation to fat in obese individuals.