Impact of bariatric surgery on circulating irisin levels: a systematic review and meta­analysis.

This systematic review and meta-analysis evaluated changes in circulating irisin levels after bariatric surgery. A systematic search was performed across Embase, Scopus, PubMed, and Web of Science for this study. The meta-analysis was conducted using Comprehensive Meta-Analysis (CMA) V4 software. The overall effect size was depicted through a random-effects meta-analysis and the leave-one-out method. The meta-analysis, which included 13 studies with a total of 407 participants, showed a statistically non-significant reduction in circulating irisin levels following bariatric surgery (SMD: - 0.089, 95% CI - 0.281, 0.102, 95% PI: - 0.790, 0.611, p = 0.360; I2:70.56). Our research found no significant change in irisin levels after bariatric surgery. Moreover, these findings were not associated with the type of surgery or the duration of follow-up.

Bariatric Surgery Improves Serum CD40L Levels as a Predictor of Cardiovascular Risk: Systematic Review and Meta-analysis.

CD40 and its ligand have been recently implicated in the pathogenesis of cardiovascular disease (CVD). This meta-analysis examined the effect of bariatric surgery in reducing circulating CD40L levels. A systematic review was performed using Embase, Google Scholar, PubMed, Scopus, and Web of Science. The meta-analysis was provided by Comprehensive Meta-Analysis (CMA) V4 software. The overall effect size was detected by a random-effects meta-analysis and the leave-one-out approach. Random-effects meta-analysis of 7 studies including 191 subjects showed a significant reduction in CD40L after bariatric surgery (standardized mean difference (SMD), - 0.531; 95% CI, - 0.981, - 0.082; p = 0.021; I2, 87.00). Circulating levels of CD40L are decreased after bariatric surgery which may represent a mechanism for improvement of metabolic profile.

Prevalence and predictors of female sexual dysfunction among sexually active women in the diabetes prevention program outcomes study.

OBJECTIVE: To determine the burden and identify correlates of female sexual dysfunction (FSD) among women with prediabetes (PreD) and type 2 diabetes (T2D) enrolled in the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS). METHODS: The DPPOS visit included the Female Sexual Function Index (FSFI) to determine sexual function. Of 1464 participants, 1320 (90%) completed the (FSFI) and 426 were sexually active. A backward selection multivariable logistic regression model estimated the odds of FSD for sociodemographic, clinical, and diabetes-related covariates. RESULTS: One hundred and eighty-five (43%) had a score of ≤26.55 and met the criteria for FSD. After adjustment for DPP treatment and age, urinary incontinence (UI) (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.15-3.17) and hysterectomy (OR = 1.89, 95% CI = 1.01-3.53) were associated with increased odds of FSD. Increased body mass index was protective for FSD (OR = 0.93 per kg/m2, 95% CI = 0.89-0.96). Michigan Neuropathy Screening Instrument-based peripheral neuropathy (mean±SD scores 1.1±1.3 vs. 0.9±1.1, p < 0.0001) and Electrocardiogram (ECG)-based autonomic dysfunction measures (mean ± SD heart rate levels 64.3 ± 6.8 vs. 65.6 ± 10.2, p = 0.008) were associated with FSD. There were no differences in diabetes rates between women who did (66.5%) and did not (66%) have (p = 0.7). CONCLUSIONS: FSD is prevalent in women with PreD and T2D. Our findings suggest that FSD is associated with neuropathic complications commonly observed in PreD and T2D.

Prevalence and predictors of erectile dysfunction among men in the diabetes prevention program outcomes study.

OBJECTIVE: To determine burden and identify correlates of erectile dysfunction (ED) among men with prediabetes (PreD) and type 2 diabetes (T2D) enrolled in the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS). RESEARCH DESIGN AND METHODS: The 2017 DPPOS visit included administration of the International Index of Erectile Function. Of 648 male participants, 88 % (n = 568) completed the survey. Associations between sociodemographic, behavioral, clinical, and glycemic measures at time of ED assessment, and ED were examined using multivariable logistic regression models in men with PreD and T2D separately. RESULTS: Overall, 218 (38 %) men met ED criteria. Prevalence was similar in men with PreD (41 %) and T2D (37 %) (p = 0.4). In all men, age (p < 0.001) increased odds of ED. Among men with PreD, those assigned to intensive lifestyle intervention (ILS), but not metformin, had decreased odds of ED compared with the placebo group (OR = 0.35, 95 % CI = 0.13, 0.94). Non-Hispanic White race was associated with increased odds of ED compared with other races (OR = 4.3; 95 % CI = 1.92, 9.65). Among men with T2D, ED risk did not differ by DPP treatment assignment; however, individuals with metabolic syndrome defined by National Cholesterol Education Program criteria, had increased odds of ED (OR = 1.85, 95 % CI = 1.14, 3.01), as did individuals with depression (OR = 2.05; 95 % CI = 1.10, 3.79). CONCLUSIONS: ED is prevalent in men with PreD and T2D. Our finding of reduced odds of ED in men randomized to ILS and with PreD suggests a potential opportunity for risk mitigation in the prediabetes interval. In men who have progressed to T2D, metabolic factors appear to be associated with ED.

Effects of testosterone enanthate on aggression, risk-taking, competition, mood, and other cognitive domains during 28 days of severe energy deprivation.

RATIONALE: Behavioral effects of testosterone depend on dose, acute versus sustained formulation, duration of administration, personality, genetics, and endogenous levels of testosterone. There are also considerable differences between effects of endogenous and exogenous testosterone. OBJECTIVES: This study was the secondary behavioral arm of a registered clinical trial designed to determine if testosterone protects against loss of lean body mass and lower-body muscle function induced by a severe energy deficit typical of sustained military operations. METHODS: Behavioral effects of repeated doses of testosterone on healthy young men whose testosterone was reduced by severe energy deficit were examined. This was a double-blind, placebo-controlled, between-group study. Effects of four weekly intramuscular injections of testosterone enanthate (200 mg/week, N = 24) or matching placebo (N = 26) were evaluated. Determination of sample size was based on changes in lean body mass. Tasks assessing aggression, risk-taking, competition, social cognition, vigilance, memory, executive function, and mood were repeatedly administered. RESULTS: During a period of artificially induced, low testosterone levels, consistent behavioral effects of administration of exogenous testosterone were not observed. CONCLUSIONS: Exogeneous testosterone enanthate (200 mg/week) during severe energy restriction did not reliably alter the measures of cognition. Study limitations include the relatively small sample size compared to many studies of acute testosterone administration. The findings are specific to healthy males experiencing severe energy deficit and should not be generalized to effects of other doses, formulations, or acute administration of endogenous testosterone or studies conducted with larger samples using tests of cognitive function designed to detect specific effects of testosterone.

Improvement of Triglyceride-Glucose Index Following Bariatric Surgery: a Systematic Review and Meta-analysis.

BACKGROUND: Bariatric surgery is an effective intervention for the management of severe obesity and its associated comorbidities, including metabolic abnormalities. This meta-analysis aimed to evaluate the impact of bariatric surgery on the triglyceride-glucose (TyG) index, a novel marker of insulin resistance and metabolic syndrome. METHODS: A systematic search was conducted in Embase, PubMed, Web of Science, and Scopus. The meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V4 software. The overall effect size was determined by a random-effects meta-analysis and the leave-one-out approach. RESULTS: A total of 9 trials including 1620 individuals confirmed a significant reduction in TyG following bariatric surgery (weighted mean difference (WMD) - 0.770, 95% CI - 1.006, - 0.534, p < 0.001). In a sub-analysis according to the type of bariatric surgery there was a significant reduction in TyG index for Roux-en-Y gastric bypass (WMD - 0.775, 95% CI - 1.000, - 0.550, p < 0.001), and sleeve gastrectomy (WMD - 0.920, 95% CI - 1.368, - 0.473, p < 0.001). In a sub-analysis according to the follow-up duration there was similarly a significant reduction in TyG index for both < 12 months (WMD - 1.645, 95% CI - 2.123, - 1.167, p < 0.001), and ≥ 12 months follow-up (WMD - 0.954, 95% CI - 1.606, - 0.303, p < 0.001). CONCLUSION: The results of this meta-analysis demonstrated a significant reduction in the TyG index following bariatric surgery, indicating improved insulin sensitivity and metabolic health. These findings highlight the potential of bariatric surgery as a valuable therapeutic option for individuals with obesity and its metabolic consequences.

Coronary Artery Calcium and Cognitive Decline in the Diabetes Prevention Program Outcomes Study.

Background Our aim was to investigate the association of coronary artery calcium (CAC) with cognitive function in adults with impaired glucose tolerance or type 2 diabetes. Methods and Results The Diabetes Prevention Program was a randomized controlled trial comparing an intensive lifestyle intervention, metformin, or placebo for prevention of type 2 diabetes among patients with prediabetes. After 3 years, intensive lifestyle intervention and placebo were stopped, the metformin arm was unmasked, and participants continued in the DPPOS (Diabetes Prevention Program Outcomes Study). Approximately 14 years after randomization (Y14), CAC (Agatston score) was assessed with computed tomography, and cognitive performance was assessed with the Spanish English Verbal Learning Test (SEVLT) and Digit Symbol Substitution Test. SEVLT and Digit Symbol Substitution Test were reassessed 5 years later (Y19) along with the Modified Mini-Mental State Exam. We examined cross-sectional and longitudinal associations between CAC and cognition among 1931 participants using linear and logistic regression. In unadjusted analyses, compared with no calcification, CAC score >300 was associated with decreased performance on all cognitive tests at Y14 in both sexes. Additionally, CAC >300 was associated with a greater 5-year decline in SEVLT Immediate Recall in both sexes and SEVLT Delayed Recall in women. After adjustment for demographic, genetic, metabolic, vascular, and behavioral covariates, CAC score >300 remained associated with greater decline in only SEVLT Delayed Recall in women. Conclusions In women with prediabetes or diabetes, CAC >300, compared with no calcification, was independently associated with greater decline in verbal memory. Registration information clinicaltrials.gov. Identifier: NCT00038727.

Analysis of Veno-Venous Extracorporeal Membrane Oxygenation for COVID-19 Compared to Non-COVID Etiologies.

OBJECTIVE: This study analyzed the characteristics and outcomes of veno-venous (V-V) extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome (ARDS) due to COVID-19 versus non-COVID causes at US academic centers. BACKGROUND DATA: V-V ECMO support has been utilized for COVID-19 patients with ARDS since the beginning of the pandemic. Mortality for ECMO in COVID-19 has been reported to be high but similar to reported mortality for ECMO support for non-COVID causes of respiratory failure. METHODS: Using ICD-10 codes, data of patients who underwent V-V ECMO for COVID-19 ARDS were compared with patients who underwent V-V ECMO for non-COVID causes between April 2020 and December 2022. The primary outcome was in-hospital mortality. Secondary outcome measures included length of stay and direct cost. Multivariate logistic regression modeling was performed to analyze differences in mortality between COVID and non-COVID groups, adjusting for other important risk factors (age, sex, and race/ethnicity). RESULTS: We identified and compared 6382 patients who underwent V-V ECMO for non-COVID causes to 6040 patients who underwent V-V ECMO for COVID-19. There was a significantly higher proportion of patients aged ≥ 65 years who underwent V-V ECMO in the non-COVID group compared with the COVID group (19.8% vs. 3.7%, respectively, P <0.001). Compared with patients who underwent V-V ECMO for non-COVID causes, patients who underwent V-V ECMO for COVID had increased in-hospital mortality (47.6% vs. 34.5%, P <0.001), length of stay (46.5±41.1 days vs. 40.6±46.1, P <0.001), and direct hospitalization cost ($207,022±$208,842 vs. $198,508±205,510, P =0.02). Compared with the non-COVID group, the adjusted odds ratio (OR) for in-hospital mortality in the COVID group was 2.03 (95% CI: 1.87-2.20, P <0.001). In-hospital mortality for V-V ECMO in COVID-19 improved during the study time period (50.3% in 2020, 48.6% in 2021, and 37.3% in 2022). However, there was a precipitous drop in the ECMO case volume for COVID starting in quarter 2 of 2022. CONCLUSIONS: In this nationwide analysis, COVID-19 patients with ARDS requiring V-V ECMO support had increased mortality compared with patients who underwent V-V ECMO for non-COVID etiologies.

Pharmacotherapy for obesity: recent evolution and implications for cardiovascular risk reduction.

INTRODUCTION: Obesity is highly prevalent in the U.S. and is associated with an increased risk of major adverse cardiovascular events (MACE). Modalities for the management of obesity include lifestyle intervention, pharmacotherapy, and bariatric surgery. AREAS COVERED: This review describes the evidence on the effects of weight loss therapies on MACE risk. Lifestyle interventions and older antiobesity pharmacotherapies have been associated with <12% body weight reduction and no clear benefit to reduce MACE risk. Bariatric surgery is associated with substantial weight reduction (20-30%) and markedly lower subsequent risk for MACE. Newer antiobesity pharmacotherapies, particularly semaglutide and tirzepatide, have shown greater efficacy for weight reduction compared with older medications and are being evaluated in cardiovascular outcomes trials. EXPERT OPINION: Current practice for cardiovascular risk reduction in patients with obesity is lifestyle intervention for weight loss, combined with the treatment of obesity-related cardiometabolic risk factors individually. The use of medications to treat obesity is relatively rare. In part, this reflects concerns about long-term safety and weight loss effectiveness, possible provider bias, as well as lack of clear evidence of MACE risk reduction. If ongoing outcomes trials demonstrate the efficacy of newer agents in reducing MACE risk, this will likely lead to expanded use in obesity management.

Weight Regain After Bariatric Surgery: Scope of the Problem, Causes, Prevention, and Treatment.

PURPOSE OF REVIEW: Although bariatric surgery is the most effective treatment of severe obesity, a proportion of patients experience clinically significant weight regain (WR) with further out from surgery. The purpose of this review is to summarize the prevalence, predictors, and causes of weight regain. RECENT FINDINGS: Estimating the prevalence of WR is limited by a lack of consensus on its definition. While anatomic failures such as dilated gastric fundus after sleeve gastrectomy and gastro-gastric fistula after Roux-en-Y gastric bypass can lead to WR, the most common causes appear to be dysregulated/maladaptive eating behaviors, lifestyle factors, and physiological compensatory mechanisms. To date, dietary, supportive, behavioral, and exercise interventions have not demonstrated a clinically meaningful impact on WR, and there is limited evidence for pharmacotherapy. Future studies should be aimed at better defining WR to begin to understand the etiologies. Additionally, there is a need for non-surgical interventions with demonstrated efficacy in rigorous randomized controlled trials for the prevention and reversal of WR after bariatric surgery.

Risk of Type 2 Diabetes Among Individuals with Excess Weight: Weight Trajectory Effects.

PURPOSE OF REVIEW: Increased risk of type 2 diabetes mellitus (T2D) among individuals with overweight or obesity is well-established; however, questions remain about the temporal dynamics of weight change (gain or loss) on the natural course of T2D in this at-risk population. Existing epidemiologic evidence is limited to studies that discretely sample and assess excess weight and T2D risk at different ages with limited follow-up, yet changes in weight may have time-varying and possibly non-linear effects on T2D risk. Predicting the impact of weight change on the risk of T2D is key to informing primary prevention. We critically review the relationship between weight change, trajectory groups (i.e., distinct weight change patterns), and T2D risk among individuals with excess weight in recently published T2D prevention randomized controlled trials (RCTs) and longitudinal cohort studies. RECENT FINDINGS: Overall, weight trajectory groups have been shown to differ by age of onset, sex, and patterns of insulin resistance or beta-cell function biomarkers. Lifestyle (diet and physical activity), pharmacological, and surgical interventions can modify an individual's weight trajectory. Adolescence is a critical etiologically relevant window during which onset of excess weight may be associated with higher risk of T2D. Changes in insulin resistance and beta-cell function biomarkers are distinct but related correlates of weight trajectory groups that evolve contemporaneously over time. These multi-trajectory markers are differentially associated with T2D risk. T2D risk may differ by the age of onset and duration of excess body weight, and the type of weight loss intervention. A better understanding of the changes in weight, insulin sensitivity, and beta-cell function as distinct but related correlates of T2D risk that evolve contemporaneously over time has important implications for designing and targeting primary prevention efforts.

Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study.

BACKGROUND: Lifestyle intervention and metformin have been shown to prevent diabetes; however, their efficacy in preventing cardiovascular disease associated with the development of diabetes is unclear. We examined whether these interventions reduced the incidence of major cardiovascular events over a 21-year median follow-up of participants in the DPP trial (Diabetes Prevention Program) and DPPOS (Diabetes Prevention Program Outcomes Study). METHODS: During DPP, 3234 participants with impaired glucose tolerance were randomly assigned to metformin 850 mg twice daily, intensive lifestyle or placebo, and followed for 3 years. During the next 18-year average follow-up in DPPOS, all participants were offered a less intensive group lifestyle intervention, and unmasked metformin was continued in the metformin group. The primary outcome was the first occurrence of nonfatal myocardial infarction, stroke, or cardiovascular death adjudicated by standard criteria. An extended cardiovascular outcome included the primary outcome or hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, coronary heart disease diagnosed by angiography, or silent myocardial infarction by ECG. ECGs and cardiovascular risk factors were measured annually. RESULTS: Neither metformin nor lifestyle intervention reduced the primary outcome: metformin versus placebo hazard ratio 1.03 (95% CI, 0.78-1.37; P = 0.81) and lifestyle versus placebo hazard ratio 1.14 (95% CI, 0.87-1.50; P = 0.34). Risk factor adjustment did not change these results. No effect of either intervention was seen on the extended cardiovascular outcome. CONCLUSIONS: Neither metformin nor lifestyle reduced major cardiovascular events in DPPOS over 21 years despite long-term prevention of diabetes. Provision of group lifestyle intervention to all, extensive out-of-study use of statin and antihypertensive agents, and reduction in the use of study metformin together with out-of-study metformin use over time may have diluted the effects of the interventions. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: DPP (NCT00004992) and DPPOS (NCT00038727).

The Role of Calorie Restriction in the Prevention of Cardiovascular Disease.

PURPOSE OF REVIEW: Calorie restriction (CR) has emerged as a non-pharmacological treatment to prevent cardiovascular disease (CVD). This article reviews recent progress regarding the role of CR in CVD prevention via reduction of cardiometabolic risk factors and promoting atherosclerotic stability. RECENT FINDINGS: Calorie restriction may be an approach to reduce the development of atherosclerosis. CR promotes eNOS activity and SIRT1 expression which in turn improves vasodilation resulting in greater regulation of blood pressure and blood flow. Modest CR in nonobese young and middle-aged adults results in improved cardiometabolic risk profile. The evidence for CR in CVD prevention has accumulated in the recent years. Most evidence, however, is from rodent or small human trials. Our understanding of the magnitude of calorie reduction that leads to the long-term therapeutic effects on cardiovascular health is limited. More well-designed controlled trials conducted in diverse populations with larger sample sizes and longer follow-ups are warranted.

Obesity, Body Composition, and Sex Hormones: Implications for Cardiovascular Risk.

Cardiovascular disease (CVD) continues to be the leading cause of death in adults, highlighting the need to develop novel strategies to mitigate cardiovascular risk. The advancing obesity epidemic is now threatening the gains in CVD risk reduction brought about by contemporary pharmaceutical and surgical interventions. There are sex differences in the development and outcomes of CVD; premenopausal women have significantly lower CVD risk than men of the same age, but women lose this advantage as they transition to menopause, an observation suggesting potential role of sex hormones in determining CVD risk. Clear differences in obesity and regional fat distribution among men and women also exist. While men have relatively high fat in the abdominal area, women tend to distribute a larger proportion of their fat in the lower body. Considering that regional body fat distribution is an important CVD risk factor, differences in how men and women store their body fat may partly contribute to sex-based alterations in CVD risk as well. This article presents findings related to the role of obesity and sex hormones in determining CVD risk. Evidence for the role of sex hormones in determining body composition in men and women is also presented. Lastly, the clinical potential for using sex hormones to alter body composition and reduce CVD risk is outlined. © 2022 American Physiological Society. Compr Physiol 12:1-45, 2022.

Effect of Metformin and Lifestyle Interventions on Mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study.

OBJECTIVE: To determine whether metformin or lifestyle modification can lower rates of all-cause and cause-specific mortality in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. RESEARCH DESIGN AND METHODS: From 1996 to 1999, 3,234 adults at high risk for type 2 diabetes were randomized to an intensive lifestyle intervention, masked metformin, or placebo. Placebo and lifestyle interventions stopped in 2001, and a modified lifestyle program was offered to everyone, but unmasked study metformin continued in those originally randomized. Causes of deaths through 31 December 2018 were adjudicated by blinded reviews. All-cause and cause-specific mortality hazard ratios (HRs) were estimated from Cox proportional hazards regression models and Fine-Gray models, respectively. RESULTS: Over a median of 21 years (interquartile range 20-21), 453 participants died. Cancer was the leading cause of death (n = 170), followed by cardiovascular disease (n = 131). Compared with placebo, metformin did not influence mortality from all causes (HR 0.99 [95% CI 0.79, 1.25]), cancer (HR 1.04 [95% CI 0.72, 1.52]), or cardiovascular disease (HR 1.08 [95% CI 0.70, 1.66]). Similarly, lifestyle modification did not impact all-cause (HR 1.02 [95% CI 0.81, 1.28]), cancer (HR 1.07 [95% CI 0.74, 1.55]), or cardiovascular disease (HR 1.18 [95% CI 0.77, 1.81]) mortality. Analyses adjusted for diabetes status and duration, BMI, cumulative glycemic exposure, and cardiovascular risks yielded results similar to those for all-cause mortality. CONCLUSIONS: Cancer was the leading cause of mortality among adults at high risk for type 2 diabetes. Although metformin and lifestyle modification prevented diabetes, neither strategy reduced all-cause, cancer, or cardiovascular mortality rates.

Effects of Cotadutide on Metabolic and Hepatic Parameters in Adults With Overweight or Obesity and Type 2 Diabetes: A 54-Week Randomized Phase 2b Study.

OBJECTIVE: Cotadutide, a dual GLP-1 and glucagon receptor agonist, is under development for nonalcoholic steatohepatitis (NASH) and chronic kidney disease with type 2 diabetes. The effects of cotadutide on hepatic and metabolic parameters were evaluated in participants with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS: In this phase 2b study, 834 adults with BMI ≥25 kg/m2 and type 2 diabetes inadequately controlled with metformin (glycated hemoglobin A1c [HbA1c] of 7.0%-10.5% [53-91 mmol/mol]) were randomized to double-blind cotadutide 100 µg (n = 100), 200 µg (n = 256), or 300 µg (n = 256); placebo (n = 110); or open-label liraglutide 1.8 mg (n = 110)-all administered subcutaneously. Coprimary end points were changes in HbA1c and body weight at week 14. The originally randomized interventions were continued to week 54. Liver damage biomarkers and liver fibrosis algorithms were assessed. RESULTS: Cotadutide significantly decreased HbA1c and body weight at weeks 14 and 54 versus placebo (all P < 0.001). Improvements in lipid profile, AST and ALT levels, propeptide of type III collagen level, fibrosis-4 index, and nonalcoholic fatty liver disease fibrosis score were observed with cotadutide 300 µg versus placebo, but not with liraglutide. Weight loss with cotadutide 200 µg was similar to that with liraglutide 1.8 mg and greater with cotadutide 300 µg versus liraglutide 1.8 mg. The most common adverse events with cotadutide (nausea, 35%; vomiting, 17%) decreased over time. CONCLUSIONS: Cotadutide treatment for 54 weeks improved glycemic control and weight loss in participants with overweight/obesity and type 2 diabetes. Ad hoc analyses demonstrated improvements in hepatic parameters and support further evaluation of cotadutide in NASH.

Testosterone supplementation upregulates androgen receptor expression and translational capacity during severe energy deficit.

Testosterone supplementation during energy deficit promotes whole body lean mass accretion, but the mechanisms underlying that effect remain unclear. To elucidate those mechanisms, skeletal muscle molecular adaptations were assessed from muscle biopsies collected before, 1 h, and 6 h after exercise and a mixed meal (40 g protein, 1 h postexercise) following 14 days of weight maintenance (WM) and 28 days of an exercise- and diet-induced 55% energy deficit (ED) in 50 physically active nonobese men treated with 200 mg testosterone enanthate/wk (TEST) or placebo (PLA) during the ED. Participants (n = 10/group) exhibiting substantial increases in leg lean mass and total testosterone (TEST) were compared with those exhibiting decreases in both of these measures (PLA). Resting androgen receptor (AR) protein content was higher and fibroblast growth factor-inducible 14 (Fn14), IL-6 receptor (IL-6R), and muscle ring-finger protein-1 gene expression was lower in TEST vs. PLA during ED relative to WM (P < 0.05). Changes in inflammatory, myogenic, and proteolytic gene expression did not differ between groups after exercise and recovery feeding. Mechanistic target of rapamycin signaling (i.e., translational efficiency) was also similar between groups at rest and after exercise and the mixed meal. Muscle total RNA content (i.e., translational capacity) increased more during ED in TEST than PLA (P < 0.05). These findings indicate that attenuated proteolysis at rest, possibly downstream of AR, Fn14, and IL-6R signaling, and increased translational capacity, not efficiency, may drive lean mass accretion with testosterone administration during energy deficit.