OBJECTIVE:Dietary protein reduction increases plasma fibroblast growth factor 21 (FGF21) and energy requirements in lean men under eucaloric conditions. Whether these metabolic effects translate to weight loss during isocaloric conditions in men with overweight or obesity remains unclear. METHODS:Seventeen men with overweight or obesity were randomly allocated to two different highly controlled, isocaloric diets for 5 weeks, receiving either a protein-reduced diet (0.9 g kg-1 BW day-1) substituted with increased carbohydrates or a habitual diet (1.8 g kg-1 BW day-1). RESULTS:Protein reduction induced a 2.0 ± 0.6 kg weight loss and increased plasma FGF21 concentration compared with higher protein intake, without caloric restriction. Changes in plasma FGF21 concentration were inversely associated with changes in body weight (r = -0.59, p = 0.02). Expression of key components in the FGF21 receptor complex, FGFR1 and β-klotho, and downstream targets in subcutaneous adipose tissue remained unchanged. Markers of skeletal muscle mitochondrial oxidative phosphorylation were also unaltered. Fat mass decreased significantly, whereas this level of protein reduction only tended to lower lean body mass. CONCLUSIONS:These findings suggest that reducing protein intake (0.9 g kg-1 BW day-1), substituted with increased carbohydrates, compared with a habitual protein intake (1.8 g kg-1 BW day-1), can induce weight loss without restricting total energy intake in men with overweight or obesity. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT06263725.
OBJECTIVE:This study assessed changes in body composition and 24-h energy metabolism at 6 and 12 months after initiation of a 1-month very low-calorie ketogenic diet (VLCKD) in women with obesity. METHODS:Seventeen women with obesity who completed a 1-month VLCKD underwent a 4-week transition phase with carbohydrate reintroduction, followed by a hypocaloric balanced diet. Assessments of body composition by dual-energy X-ray absorptiometry (DXA) and 24-h energy expenditure (24hEE) by a whole-room indirect calorimeter were performed. RESULTS:Following the initial 7% weight loss, body weight further decreased at 6 months (-3.9%, p < 0.05), primarily driven by a significant decrease in fat mass (-10%, p < 0.05). From 6 to 12 months, three participants continued to lose weight, whereas most remained stable or partially regained. Lean soft tissue, decreased during the VLCKD phase, remained stable throughout follow-up. Both 24hEE and 24-h sleeping metabolic rate exhibited a progressive trend toward increase. Minute-by-minute 24hEE trajectories revealed a significant increase in metabolic rate from 1 to 6 months (p < 0.001). The metabolic adaptation observed after 1 month of VLCKD was no longer detectable at either 6 or 12 months. CONCLUSIONS:These findings provide novel insight into the physiological adaptations following VLCKD, supporting its role in supervised weight loss programs for selected patients. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT07418281.
OBJECTIVE:SURMOUNT-REAL UK will evaluate the effectiveness of tirzepatide when offered in addition to standard-of-care (SoC) in adults with Class I obesity (BMI ≥ 30 and ≤ 34.9 kg/m2) and without diabetes in a UK primary care setting. METHODS:A 5-year, phase 4, multicenter, open-label, pragmatic randomized clinical trial is enabled through access to participants' integrated electronic healthcare record data. The study will enroll approximately 3000 participants from Greater Manchester, UK, who are randomly assigned in a 1:1 ratio to receive either tirzepatide and SoC or SoC alone. RESULTS:The primary endpoint is the percent change in body weight from baseline to Month 24, with the time to onset of type 2 diabetes to Month 60 being the key secondary endpoint. Additional endpoints include the impact of tirzepatide versus SoC on obesity-related complications, health-related quality of life, healthcare resource utilization, productivity, employment, and sickness-related absences. CONCLUSIONS:SURMOUNT-REAL UK employs a novel study design to evaluate real-world health outcomes and potential long-term benefits for both participants and the healthcare system associated with the delivery of pharmacological obesity treatment at a population level. The study is intended to generate critical evidence to support informed decision-making in obesity management, clinical guideline development, and healthcare policy. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT07247084.
OBJECTIVE:This study assessed the impact of sex and age on weight loss outcomes in patients receiving tirzepatide in real-world clinical practice. METHODS:We conducted a retrospective cohort study of adults with overweight or obesity who initiated tirzepatide at Mayo Clinic between June 2022 and May 2024 and completed ≥ 12 months of continuous therapy. Primary outcome was total body weight loss percentage (TBWL%) at 15 months, stratified by sex and age groups (≤ 45, 46-59, ≥ 60 years). RESULTS:Among 1039 patients (57% women; mean age 56 ± 11 years), women achieved significantly greater TBWL% than men after 15 months of treatment (15.1% vs. 10.7%, p < 0.001). Patients aged ≤ 45 years had greater weight loss than those ≥ 60 years (15.1% vs. 12.3%, p = 0.024). In multivariable analyses, greater weight loss was independently associated with female sex, absence of type 2 diabetes, no prior obesity medication use, no concomitant weight gain-promoting medications, and higher tirzepatide dosage. Age was not an independent predictor. CONCLUSIONS:Sex, but not age, predicted weight loss with tirzepatide among individuals using the medication continuously for ≥ 12 months. These findings underscore the importance of incorporating sex-specific considerations into personalized obesity treatment strategies.
OBJECTIVE:Obesity, a critical public health challenge, involves dysregulated food stimuli responses central to its pathophysiology. Aversion to harmful food is protective, but dynamic brain network reorganization during aversion processing in obesity and its clinical implications remain inadequately understood. METHODS:Brain activity was recorded from 30 participants with obesity and 35 healthy participants during exposure to spoiled food videos in an MRI scanner. We applied dynamic network analysis to assess obesity-related alterations in neural circuits and their links to eating disorders. RESULTS:The group with obesity showed significantly lower integration between the visual (VN), dorsal attention (DAN), and subcortical (SUB) networks than the healthy control group while viewing spoiled food videos. Critically, this DAN-SUB integration correlated positively with body image distress and negatively with craving ratings, and it moderated the predictive link between cognitive impulsivity and eating disorders. Granger causality analysis confirmed a dominant indirect pathway with stronger effective connectivity, showing differential spatial associations with neurotransmitter receptors (α4β2, mGluR5, NMDA, and CB1). CONCLUSIONS:This study reveals VN-DAN-SUB dynamic interactions in aversion processing, emphasizing the indirect pathway's key role. Inefficient VN-DAN-SUB coordination in obesity may impair aversive food stimuli regulation, supporting the emotion regulation deficit hypothesis and offering a neurobiological basis for future interventions.
OBJECTIVE:Approximately 41% of the US population has obesity, though the prevalence of the highest BMI populations (e.g., ≥ 60 kg/m2) is increasing most rapidly. Given the association between obesity and surgical disease burden, we hypothesized that higher BMI groups would account for a growing proportion of operative volume over time. This study examined whether individuals with higher BMI have been receiving proportionally more surgical care over time. METHODS:All multispecialty National Surgical Quality Improvement Program (NSQIP) cases from 2005 to 2022 were analyzed (n = 11,634,075). Multinomial logistic regression was performed to analyze trends among BMI categories (< 30.0, 30.0-39.9, 40.0-49.9, 50.0-59.9, 60.0-69.9, and ≥ 70 kg/m2), while adjusting for demographics and comorbidities. RESULTS:Regression models demonstrated decreased odds of patients with BMI ≥ 50 kg/m2 undergoing surgery over consecutive years, with increasingly higher BMI groups representing greater declines. Patients with BMI 30.0-39.9 kg/m2 demonstrated increased proportional operative volume. CONCLUSIONS:Despite increased growth in higher BMI populations, individuals in these categories undergo fewer surgical operations annually. These findings demonstrate a critical need to understand these inequalities, which are underscored by rising obesity prevalence that may be contributing to poor access to surgical care as well as increased morbidity/mortality of presentation with more advanced disease.
OBJECTIVE:Use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has increased rapidly following approval for obesity treatment, but data on their use in younger populations remain limited. We examined trends in GLP-1RA use among 12- to 24-year-olds in Denmark during 2018-2025. METHODS:Using nationwide prescription, hospital, and laboratory registries, we conducted a drug utilization study including all 12- to 24-year-olds who filled a GLP-1RA prescription between January 2018 and December 2025. We described incidence of use, baseline characteristics, prescribing patterns, and treatment persistence. RESULTS:GLP-1RA use rose more than 50-fold across the study period, reaching 418 new users per 100,000 by 2025, driven by semaglutide for weight management. Uptake was steepest among individuals aged 18-24 years (from 13 to 686 per 100,000) and more modest among adolescents aged 12-17 years (from 1.7 to 72 per 100,000). Most users were female, few had diabetes, and 33% had psychiatric comorbidity, particularly emotional and neurodevelopmental disorders. By 2025, 78% of new treatments were initiated in general practice. Only 38% were covered by a prescription after 1 year. CONCLUSIONS:Findings demonstrate rapid uptake of GLP-1RAs in youth and the need for specialist involvement, long-term safety data, and careful evaluation of mental health in this population.
OBJECTIVE:This study evaluated changes in weight status and cardiometabolic parameters following bariatric surgery (BS) among adolescents with obesity using population-based real-world data. METHODS:This retrospective cohort study used electronic health records from Clalit Health Services, Israel. Adolescents aged 12-20 years who underwent BS between 2010 and 2024 were included. Demographic characteristics, socioeconomic position (SEP), anthropometry, blood pressure, and laboratory parameters were extracted. Longitudinal changes in BMI and cardiometabolic outcomes were analyzed using mixed-effects models adjusted for sex, ethnicity, SEP, age at BS, and baseline BMI. Median follow-up was 5.8 years. RESULTS:The cohort included 1035 adolescents (69.7% female; median age at surgery ~18.6 years), with sleeve gastrectomy as the predominant procedure. BMI declined significantly over time (p time < 0.001), with maximal reduction at 1-3 years and sustained improvement thereafter. Males experienced greater BMI reduction than females (p time×sex < 0.001). BMI trajectories were similar across SEP and ethnic groups, while individuals with higher baseline BMI maintained higher BMI throughout follow-up (p group < 0.001). Blood pressure and multiple metabolic parameters improved substantially, with durable long-term benefits and some sex-specific differences. CONCLUSIONS:Adolescent BS was associated with sustained improvements in BMI and cardiometabolic risk factors in a large real-world cohort, supporting its long-term effectiveness across population subgroups.
OBJECTIVE:Adults with Down syndrome (DS) often show elevated systemic inflammation, but the association with obesity, aging, and Alzheimer's disease (AD) pathology is not well understood. METHODS:Data were drawn from 188 nondemented adults with DS participating in the Alzheimer Biomarkers Consortium-DS (ABC-DS). Participants completed clinical assessments, blood draws, and neuroimaging. Plasma biomarkers included indicators of general, pro-, and anti-inflammation. Mixed linear models tested associations between BMI, age, PET-measured amyloid burden, and inflammatory biomarkers, adjusting for sex, trisomy type, and collection site. False discovery rate correction was applied. RESULTS:The majority of the participants met criteria for obesity. Higher BMI was significantly associated with elevated levels of CRP, IL-6, TNF-α, B2M, IL-18, and slCAM-1 (p < 0.05). Older age was significantly associated with higher B2M (β = 1.22e + 05, p < 0.001). Amyloid burden was positively associated with IL-6 (β = 0.005, p = 0.037). CONCLUSIONS:Obesity, aging, and amyloid burden relate to systemic inflammation in adults with DS. Obesity showed the strongest and most consistent associations, emphasizing the value of regular monitoring and weight management strategies to help reduce inflammation. Aging and early amyloid accumulation showed more limited links with systemic inflammation; future work should examine whether these processes are more closely related to biomarkers of neuroinflammation as AD progresses.
Diagnosing endogenous autonomous hypercortisolism, spanning from autonomous cortisol secretion to overt Cushing syndrome, remains challenging because of the heterogeneous clinical presentation and the variability of cortisol secretion patterns. Emerging biochemical tools aim to refine and support this diagnostic process. In this review, we examine approaches to enhance classical tests, including measurement of dexamethasone concentrations during the dexamethasone suppression test, as well as newer biomarkers such as salivary cortisone, hair cortisol, metabolomic signatures in plasma and urine, and other omics-based techniques for the detection of hypercortisolism.
Endogenous hypercortisolism remains a high-stakes diagnostic challenge in which delays or misclassification drive excess morbidity and mortality. This chapter synthesizes an evidence-based, physiology-anchored approach to the differential diagnosis of ACTH-dependent Cushing's syndrome, integrating clinical phenotyping, first-line biochemistry, dynamic testing, imaging, and invasive confirmation. We first outline bedside features that raise or lower the pre-test probability of Cushing disease (CD) versus ectopic ACTH syndrome (EAS). Then, the initial laboratory tests (nocturnal salivary cortisol, 24-h urinary free cortisol, low-dose dexamethasone suppression, ACTH) and their pathophysiological correlates are reviewed. For dynamic tests, we summarize indications and interpretation of CRH, desmopressin, and high-dose dexamethasone suppression, highlighting their value as composites rather than stand-alone arbiters. The imaging section prioritizes 3 T dynamic pituitary MRI for CD and thin-slice CT for suspected EAS, with targeted use of ^68Ga-SSTRPET/CT (ectopic NETs), ^18F-FDG (high-grade biology), ^18F-DOPA (PPGL), and emerging pituitary-targeted PET tracers as adjuncts. When non-invasive data are discordant or indeterminate, bilateral inferior petrosal sinus sampling (BIPSS) remains the reference: verify selectivity (prolactin IPS:peripheral > 1.8) and apply ACTHIPS:peripheral cut-offs (≥ 2 basal or ≥ 3 post-stimulus), with optional optimized thresholds and prolactin-adjusted ratios in suboptimal flow. Finally, we propose a step-by-step diagnostic algorithm that sequences these elements pragmatically and discuss predictive models as complementary tools to prioritize testing and resource use.
Cushing´s syndrome (CS) is a heterogeneous disorder characterized by chronic exposure to cortisol excess, leading to significant metabolic and cardiovascular complications. Timely diagnosis is crucial to reduce morbidity and mortality in these patients. Approximately 20 percent of endogenous CS cases are adrenocorticotropic hormone (ACTH)-independent and arise from primary adrenal disease. This review focuses on the diagnostic work-up and etiological spectrum of ACTH-independent CS. ACTH-independent CS most frequently results from unilateral adrenal adenomas, whereas adrenocortical carcinomas represent a less common but aggressive cause. Bilateral forms include primary pigmented nodular adrenocortical disease and primary bilateral macronodular adrenal hyperplasia, which present micronodular or macronodular adrenal enlargement, respectively, often with subtle or cyclic cortisol excess and characteristic imaging patterns. Recognizing these entities and integrating hormonal data with detailed radiological findings is essential for accurate etiological diagnosis and appropriate therapeutic planning in ACTH-independent CS. Radiological assessment with adrenal computed tomography, complemented by magnetic resonance imaging when needed, is crucial to distinguish unilateral from bilateral disease, characterize lesion morphology, and suggest specific etiologies, using unenhanced attenuation values in Hounsfield units to differentiate lipid-rich adenomas from non-adenomatous or potentially malignant lesions.
Cushing's syndrome comprises a heterogeneous group of disorders characterized by chronic excess of glucocorticoid release from adrenal glands, caused by altered adrenal function or by ACTH hypersecretion from pituitary or ectopic sources. Advances in high-throughput molecular profiling have substantially refined our understanding of the mechanisms underlying endogenous hypercortisolism. This chapter provides an integrated overview of the genetic, transcriptomic, and epigenetic alterations driving both ACTH-dependent and ACTH-independent forms of the disease. Hypothalamic-pituitary-adrenal axis regulation of cortisol homeostasis is controlled by complex feedback circuits involving glucocorticoid receptor signaling, transcriptional POMC regulation, and multilayered neuroendocrine inputs. Disruption of these regulatory networks represents a central event in disease pathogenesis. In corticotroph adenomas, recurrent somatic mutations in USP8, USP48, and BRAF converge on enhanced POMC transcription and ACTH secretion, while aggressive tumors frequently harbor alterations in TP53 and ATRX. Transcriptomic and spatial profiling reveal lineage-defined tumor identities alongside significant intratumoral heterogeneity, whereas epigenetic mechanisms-including DNA methylation, miRNA dysregulation, and chromatin remodeling-fine-tune hormone secretion and glucocorticoid feedback resistance. Ectopic ACTH-secreting neuroendocrine tumors exhibit a distinct molecular profile characterized by epigenetic reactivation of POMC through promoter hypomethylation and context-dependent transcriptional reprogramming, independent of canonical pituitary lineage factors. In contrast, ACTH-independent Cushing's syndrome is predominantly driven by constitutive activation of the cAMP/PKA pathway in adrenal lesions, most commonly through activating PRKACA mutations, with additional contributions from GNAS and CTNNB1. Adrenocortical carcinoma displays a more complex genomic landscape involving IGF2 overexpression, Wnt/β-catenin activation, and tumor suppressor alterations, reflecting its malignant phenotype. These molecular insights have direct clinical implications, enabling refined disease classification, improved prognostic stratification, and the identification of actionable therapeutic targets, including EGFR, MAPK, PKA, and glucocorticoid receptor-associated pathways. Collectively, the integration of multi-omics approaches is redefining the conceptual framework of Cushing's syndrome and paving the way toward precision medicine strategies in endocrine oncology.
Cushing's syndrome (CS) during pregnancy is an exceptionally rare but high-risk condition that poses major diagnostic and therapeutic challenges. Its low prevalence is mainly due to cortisol-induced infertility. Although its low prevalence stems primarily from cortisol-induced infertility, an increasing number of cases are being recognized due to enhanced clinical awareness and expanded use of assisted reproductive technologies. In contrast to the general population where pituitary adenomas predominate, pregnancy-associated CS demonstrates a distinct etiology pattern, with ACTH-independent causes accounting for the majority of cases, particularly benign adrenal adenomas. The physiological hypercortisolism of gestation complicates diagnostic testing, as urinary free cortisol and late-night salivary cortisol rise up to threefold, although circadian rhythmicity is usually preserved. Clinical features overlapping with normal pregnancy delay recognition, but specific signs such as wide violaceous striae, proximal myopathy, and easy bruising should raise suspicion. Untreated CS carries a markedly increased risk of maternal morbidity, including preeclampsia, diabetes, infections, and thromboembolic events, and adverse fetal outcomes such as prematurity, growth restriction, and fetal loss. Management requires a multidisciplinary team. Surgery in the second trimester, remains the treatment of choice. Medical therapy, mainly with metyrapone, may be considered in selected severe cases, whereas ketoconazole and cabergoline have more limited roles. Drugs such as mitotane and mifepristone are contraindicated during pregnancy, while osilodrostat lacks clinical evidence. In summary, early recognition and individualized management are essential to optimize maternal and fetal outcomes in this rare but high-risk condition.
ectopic Cushing syndrome (ECS) is a rare endocrinological disease caused by neuroendocrine tumors capable of secreting ATCH or POMC derived immature peptides. It accounts for 10-20 percent of Cushing syndrome cases. ACTH secretion usually leads to clinically severe hypercortisolism with a predominance of glucocorticoids catabolic effects on clinical presentation. It has been suggested that ECS should be divided into two phenotypes, aggressive and indolent. The first one is characterized by classical Cushingoid features, like weight gain, purple striae and so on. The latter is characterized by underlying tumor progression with more pronounced glucocorticoid catabolic effect on muscles, bones and skin tissues. Time from symptoms onset to diagnosis and survival can be reduced in ECS compared to other Cushing syndrome (CS) etiologies. ECS diagnosis can be challenging and is based on four points: clinical suspicion, hypercortisolism confirmation, differential diagnosis with pituitary Cushing (Cushing disease; CD) and tumor localization. All available screening tools for hypercortisolism are used in ECS with good sensitivity and specificity. Between the most used dynamic tests there are: CRH stimulation test, desmopressin test and high dose dexamethasone suppression test (HDDST); inferior petrosal sinus sampling (IPSS) is considered the gold standard for differential diagnosis. CT scan, MRI and functional imaging using radionuclide labelled tracers can help in localizing the responsible tumor even if smaller tumors can become radiologically evident only during follow-up. Circulating Mi-RNAs sequencing and machine learning algorithms may also help in the future for differential diagnosis and therapy personalization.
Hypercortisolism constitutes several symptoms and signs due to inappropriately high and prolonged exposure to excess glucocorticoids (GCs), known as Cushing's syndrome (CS). While iatrogenic corticosteroid administration is the most frequent cause of CS, pituitary corticotroph adenoma, is the most common cause of endogenous excessive GC secretion. Since chronic exposure to high GC levels has been associated with an increased multisystemic morbidity and mortality, prompt identification and treatment are mandatory to minimize long-term complications. The main abnormalities and diagnostic biochemical tests to evaluate cortisol secretion include loss of the normal circadian rhythm assessed by late night salivary cortisol, reduced GC feedback assessed by overnight 1mg dexamethasone suppression test and elevated levels of biologically active cortisol measured by 24-h urinary free cortisol. This chapter addresses the biochemical diagnosis of hypercortisolism. It outlines when to suspect the condition, which biochemical tests are recommended and how they should be performed, providing tools and recommendations for the initial biochemical evaluation. It also discusses challenges, potential pitfalls, and accuracy of each test to aid interpretation and optimize their clinical use.
Endogenous Cushing's syndrome (CS) is characterized by chronic glucocorticoid excess that drives a severe cardiometabolic phenotype responsible for most morbidity and mortality associated with the disorder. Cortisol excess induces a constellation of metabolic derangements-including visceral adiposity, insulin resistance, hypertension, dyslipidemia, and ectopic fat deposition-that closely mirror and amplify the components of metabolic syndrome. These abnormalities result from widespread glucocorticoid actions on adipose tissue, liver, skeletal muscle, pancreas, vasculature, and the heart, mediated through genomic, nongenomic, and local tissue-specific mechanisms such as altered AMPK signaling and dysregulated 11β-HSD activity. Cardiovascular disease represents the leading cause of death in CS, with increased risks of myocardial infarction, stroke, heart failure, and venous thromboembolism. Structural and functional cardiovascular changes-including arterial stiffness, endothelial dysfunction, concentric left ventricular hypertrophy, myocardial fibrosis, and coronary microvascular impairment-are frequently observed and often only partially reversible. Although biochemical remission leads to improvement in many metabolic and cardiovascular parameters, substantial residual cardiometabolic risk persists, with high rates of persistent hypertension, dyslipidemia, glucose abnormalities, central adiposity, and prothrombotic imbalance. Long-term mortality remains elevated even decades after cure, particularly in patients with prolonged hypercortisolism or coexisting cardiometabolic disease. The recognition that overt CS constitutes an accelerated model of metabolic syndrome underscores the need for early diagnosis, prompt cortisol normalization, and aggressive long-term management of cardiovascular and metabolic comorbidities.
Cushing's syndrome (CS) presents with a constellation of features reflecting chronic glucocorticoid excess. Hallmarks-central adiposity with thin extremities, dorsocervical and supraclavicular fat pads, round facies with plethora, wide violaceous striae, skin fragility, acne or hirsutism, and proximal myopathy-often coexist with systemic complications that drive morbidity and mortality. Phenotype and evolution vary by etiology: Cushing's disease typically evolves insidiously and may cycle, whereas ectopic ACTH secretion often presents abruptly with severe hypercortisolism, hypokalemic metabolic alkalosis, profound protein catabolism, and heightened infection risk. Adrenal forms range from overt CS to mild autonomous cortisol secretion, with attenuated stigmata yet meaningful cardiometabolic burden. Age and sex modulate expression: children frequently show growth deceleration with weight gain; older adults exhibit sarcopenic obesity, osteoporosis, and cardiovascular disease; men may develop hypogonadism, and women menstrual dysfunction. The comorbidity spectrum spans hypertension, insulin resistance, atherogenic dyslipidemia, and hepatic steatosis; venous thromboembolism due to a prothrombotic milieu; skeletal fragility with vertebral fractures; immune dysregulation predisposing to serious infections; and neuropsychiatric and cognitive sequelae that impair quality of life and can persist after biochemical remission. This chapter synthesizes contemporary evidence to (i) highlight red-flag patterns that shorten diagnostic latency; (ii) link pathophysiologic axes to multisystem complications; and (iii) offer practical screening and initial management clues for high-risk populations (e.g., refractory hypertension, difficult-to-control diabetes), to reduce the long-term health burden of hypercortisolism.
