Manfredi Rizzo

Body mass index (BMI) is widely used in clinical practice, but it does not directly reflect fat distribution, ectopic adiposity, or adipose tissue function. Individuals with a normal or near-normal BMI may still have excess visceral fat. The Thin Outside, Fat Inside (TOFI) phenotype describes this mismatch between external body size and internal adiposity. This structured narrative review examined TOFI and related normal-weight phenotypes, focusing on visceral and ectopic fat, adipose tissue dysfunction, molecular mechanisms, imaging, and organ-specific risk. A literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science for English-language studies published mainly between 2021 and 2026. Earlier seminal and directly relevant studies were also included. Evidence from related human phenotypes and experimental models suggests that impaired adipose tissue expandability, visceral and ectopic fat accumulation, inflammation, mitochondrial stress, and lipotoxicity may help explain metabolic dysfunction despite a normal BMI. These mechanisms remain incompletely characterized in populations explicitly defined as TOFI. Preclinical models and imaging methods may help characterize TOFI-like features. Diagnostic criteria are still heterogeneous, and TOFI-specific longitudinal and intervention data remain limited. TOFI may serve as a useful translational framework for identifying hidden adiposity and metabolic risk in individuals with a normal BMI.

Ectopic Cushing’s syndrome (ECS) causes 10% to 20% of all cases of endogenous hypercortisolism. It is caused by the aberrant secretion of adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH) due to the presence of an ectopic tumor. The latter is usually a neuroendocrine (NEN) tumor (mostly thoracic NENs such as bronchial NEN neoplasms, thymic NEN neoplasms, small cell lung carcinoma (SCLC), or pancreatic NEN neoplasms). Clinical presentation is heterogeneous: an aggressive phenotype, typically driven by rapidly growing, poorly differentiated tumors such as small-cell lung carcinoma, manifests with severe symptoms of acute onset, predominant myopathy, resistant arterial hypertension, hypokalemia, and severe hyperpigmentation, usually without the centripetal obesity typical of Cushing’s syndrome; conversely, an indolent phenotype, more often related to well-differentiated neuroendocrine neoplasms such as bronchial carcinoids, may present with the classic centripetal fat distribution, facial plethora, and purple striae also seen in Cushing’s disease, making clinical distinction between the two difficult. The diagnosis of ECS can be cumbersome and time-consuming. Once hypercortisolism is confirmed, the most critical step is to distinguish patients with an ectopic source of ACTH from those with pituitary adenoma. Dynamic endocrine tests such as the high-dose dexamethasone suppression test, CRH stimulation tests, desmopressin tests, and bilateral inferior petrosal sinus sampling (BIPSS) can be helpful in the differential diagnosis. BIPSS is considered the gold standard for distinguishing a pituitary from a non-pituitary source of ACTH: the absence of a central-to-peripheral ACTH gradient supports, but does not by itself localize or confirm, an ectopic source. Tumor localization is achieved by a multimodality imaging protocol, including initial high-resolution computed tomography (CT) scans, followed by functional imaging, mainly Gallium-68-labeled somatostatin receptor positron emission tomography (PET)/CT scans. However, in 10–20% of these patients, the tumors cannot be localized. The treatment of ACTH-dependent hypercortisolism is two-fold: one is to immediately control hypercortisolism to prevent life-threatening complications (opportunistic infections and thromboembolism), and the second is to definitively treat the tumor. Medical treatment with steroidogenesis inhibitors, including metyrapone, ketoconazole, and osilodrostat, or surgical management (bilateral adrenalectomy) can be effective in immediately controlling hypercortisolism. Definitive surgical resection of the tumor is the hoped-for final treatment. The prognosis is variable, depending on the nature of the underlying neoplasm, ranging from excellent in patients with resected bronchial carcinoids to dismal in those with SCLC.

Incretin and multi-receptor agonist therapies have delivered the widest range of cardiometabolic benefit of any pharmacological class in a generation, with documented benefit across obesity, type 2 diabetes, cardiovascular and renal outcomes, heart failure with preserved ejection fraction, obstructive sleep apnea, and metabolic-dysfunction-associated steatohepatitis. A substantial fraction of the cardiovascular benefit is weight independent. The pivotal trial evidence is now mature, extending to the dedicated tirzepatide cardiovascular outcome program. The clinical and system-level processes that govern long-term cardiovascular and metabolic benefit, however, lie largely outside the efficacy envelope that these trials measure. Real-world persistence is approximately one-third at 12 months in non-diabetic obesity. Discontinuation is dominated by cost rather than therapeutic failure. Weight and cardiometabolic gains revert toward baseline within months of abrupt cessation. Cyclical use has emerged as a common real-world pattern among adults who discontinue and then restart therapy. Our review proposes a lifecycle framework that organizes the evidence along the patient journey from initiation through titration, on-treatment trajectory, adverse-event landscape, persistence, discontinuation, and reinitiation. Tirzepatide serves as the analytical center of gravity; the selective GLP-1 receptor agonist literature serves as the mature comparator. Seven analytical positions are advanced, and five specific trial designs are named as the research agenda the field requires, four of which remain unaddressed. The work ahead is to align trials, prescribing pathways, and access systems with the chronic-pharmacotherapy reality of the class.

Background/Objectives: Overweight and obesity are major drivers of cardiometabolic dysfunction and increase the risk of type 2 diabetes (T2DM)and cardiovascular disease. Although lifestyle intervention remains the cornerstone of treatment, complementary strategies may provide additional benefits. The effects of Glucoerb^® and Epavin^®, administered individually or in combination, on cardiometabolic health in adults with overweight or obesity remain poorly characterized. Methods: In this prospective real-world study, 150 adults received Glucoerb^® (n = 50), Epavin^® (n = 50), or their combination (n = 50), alongside individualized nutritional counselling based on a moderately carbohydrate-restricted Mediterranean diet and standardized physical activity recommendations. Anthropometric, body composition, biochemical, and vascular parameters were assessed at baseline and after 3 months. Results: All groups showed significant improvements in body weight, body mass index (BMI), waist circumference, and fat mass (FM) (all p < 0.001). Glucoerb^® supplementation was associated with a significant reduction in HOMA-IR (−21%), whereas Epavin^® supplementation improved the lipid profile (total cholesterol −13%, triglycerides−13%, LDL cholesterol −17%, HDL cholesterol +6%). Fatty Liver Index decreased across all groups (Glucoerb^® −14%, Epavin^® −19%, combination −17%). Combined supplementation was associated with reductions in body weight (−6%) and HOMA-IR (−32%), while endothelial function improved (+19%, p = 0.017). Conclusions: These findings support further investigation of complementary multi-target plant-based strategies for cardiometabolic risk management.

Cellular stress is not inherently detrimental; its biological consequences depend on intensity, duration, context, and the capacity for recovery. This narrative review proposes the Burn-ON/Burn-OUT paradigm as a hypothesis-generating framework describing the transition from adaptive cellular activation to progressive loss of cellular resilience. A structured literature search was conducted for English-language articles published between 2021 and 2026 in PubMed, Web of Science, and Scopus, focusing on cellular stress adaptation, mitochondrial dysfunction, integrated stress response, autophagy and mitophagy, redox signaling, inflammasome activation, metabolic flexibility, senescence, and nutritional modulation. In the proposed model, Burn-ON represents a state of increased cellular demand in which mitochondrial adaptation, stress-response signaling, autophagic quality control, redox homeostasis, and metabolic flexibility remain sufficiently preserved to sustain function and allow recovery. With persistent or repetitive stress, these adaptive mechanisms may progressively lose reversibility, defining a potential tipping point toward Burn-OUT. Burn-OUT is characterized conceptually by impaired mitochondrial quality control, reduced energetic reserve, defective autophagic flux, persistent inflammatory signaling, redox imbalance, metabolic inflexibility, and loss of functional recovery, with senescence or regulated cell death representing possible downstream outcomes. Nutrition and lifestyle may modulate this continuum by influencing nutrient sensing, substrate load, mitochondrial metabolism, autophagy, and inflammatory pathways. The Burn-ON/Burn-OUT model frames cellular stress as a double-edged biological process, in which adaptation and dysfunction represent different positions along a dynamic continuum. Longitudinal studies are needed to determine whether recovery kinetics and multidimensional biomarker profiles can distinguish these proposed states.

Body mass index (BMI) is widely used in clinical practice, but it does not directly reflect fat distribution, ectopic adiposity, or adipose tissue function. Individuals with normal or near-normal BMI may still have excess visceral fat. The Thin Outside, Fat Inside (TOFI) phenotype describes this mismatch between external body size and internal adiposity. This structured narrative review examined TOFI and related normal-weight phenotypes, focusing on visceral and ectopic fat, adipose tissue dysfunction, molecular mechanisms, imaging, and organ-specific risk. A literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science for English-language studies published mainly between 2021 and 2026. Earlier seminal and directly relevant studies were also included. Current evidence suggests that TOFI-related biology may involve visceral, hepatic, pancreatic, epicardial, perivascular, and intramuscular fat, along with impaired adipose tissue expandability, hypoxia, inflammation, adipokine imbalance, mitochondrial stress, lipotoxicity, and insulin resistance. Preclinical models and imaging methods may help characterize TOFI-like features. Diagnostic criteria are still heterogeneous, and TOFI-specific longitudinal and intervention data remain limited. TOFI may serve as a useful translational framework for identifying hidden adiposity and metabolic risk in people with normal BMI.

Osteoporosis is a major skeletal disorder. Increasing evidence suggests that gut microbiota-derived mechanisms may contribute to bone remodeling. The biological rationale for a gut–bone axis is well supported, but the clinical relevance of microbiome-targeted interventions remains uncertain. In this narrative review, we focus on prebiotics, probiotics, synbiotics, and postbiotics. We searched in the literature the progress from mechanistic observations to measurable skeletal outcomes in humans. We searched PubMed, Scopus, and Web of Science for literature published mainly between 2021 and 2026. We also included earlier studies when they were important for the mechanistic framework. The evidence was evaluated according to intervention type and outcome. We focused on bone turnover markers, bone mineral density, and the duration of exposure required for these outcomes to become clinically meaningful. Recent randomized trials and meta-analyses were also compared in a semi-quantitative synthesis to show where findings are consistent and where they remain conflicting.

Mesenteric panniculitis (MP) is an uncommon inflammatory disorder of mesenteric adipose tissue. Its pathophysiology remains unclear. Gut dysbiosis, intestinal barrier dysfunction, metabolic endotoxemia, glycemic variability (GV), and vascular dysfunction have been implicated in inflammatory and metabolic disorders, but their specific involvement in MP has not been established. This narrative review integrates MP-specific clinical evidence with indirect mechanistic evidence from related metabolic, inflammatory, and experimental settings to examine the possible relationships between these mechanisms and MP and their integration within a proposed gut–mesentery–metabolic axis. The literature was reviewed through structured searches of PubMed, Scopus, and Web of Science for relevant publications from 2018 to 2026, supplemented by earlier foundational studies identified through reference-list screening and targeted searches. Current data suggest that dysbiosis and impaired intestinal barrier function may facilitate microbial-product translocation and lipopolysaccharide-mediated inflammatory signaling, while GV may contribute to oxidative stress, endothelial dysfunction, and pro-inflammatory responses. Mesenteric vascular anatomy and impaired regional perfusion may represent additional factors influencing local tissue susceptibility. Recent randomized controlled trials of microbiome-targeted interventions in metabolic disorders have shown heterogeneous effects on glycemic, inflammatory, and microbiota-related outcomes, indicating a need for further investigation of individualized microbiome-directed strategies. Direct evidence that microbial, metabolic, or vascular mechanisms initiate or sustain MP is currently limited. Accordingly, the proposed gut–mesentery–metabolic axis should be interpreted as a hypothesis-generating framework rather than an established causal model. Prospective MP-specific studies integrating microbiome profiling, validated measures of intestinal barrier function, metabolic phenotyping, GV, vascular assessment, and imaging are required to test the proposed relationships.

Endothelial dysfunction is a key mechanism linking obesity, metabolic disturbances, and cardiovascular disease, contributing to the development and progression of atherosclerosis and other vascular complications. This review provides a comprehensive overview of the molecular mechanisms underlying endothelial dysfunction in obesity and discusses current diagnostic approaches and therapeutic strategies aimed at restoring vascular homeostasis. The available evidence indicates that chronic inflammation, oxidative stress, insulin resistance, reduced nitric oxide bioavailability, increased reactive oxygen species production, and dysregulated adipokine signaling play central roles in endothelial impairment. Recent advances in functional vascular assessment, circulating biomarkers, and imaging techniques have improved the early identification of endothelial dysfunction and cardiovascular risk. Current therapeutic strategies include pharmacological agents, such as glucagon-like peptide-1 receptor agonists, sodium-glucose co-transporter 2 inhibitors, metformin, and dipeptidyl peptidase-4 inhibitors, together with lifestyle interventions based on healthy dietary patterns and regular aerobic and resistance exercise. These approaches improve glycemic control, reduce inflammation and oxidative stress, enhance endothelial function, and contribute to cardiovascular protection. Overall, the evidence supports an integrated and personalized management strategy targeting both metabolic and vascular abnormalities to reduce cardiovascular risk and improve long-term clinical outcomes in individuals with obesity.

Mesenteric panniculitis (MP) is an uncommon inflammatory disorder of mesenteric adipose tissue. Its pathophysiology remains unclear. Gut dysbiosis, intestinal barrier dysfunction, metabolic endotoxemia, glycemic variability (GV), and vascular dysfunction are involved in inflammatory and metabolic processes. These may also affect visceral and mesenteric adipose tissue. This narrative review examines the possible relationships among these mechanisms and mesenteric panniculitis and discusses their integration within a proposed gut–mesentery–metabolic axis. The literature was reviewed using PubMed, Scopus, Web of Science, and Google Scholar, including studies published between 2000 and 2026. We focus on recent evidence published between 2021 and 2026. Current data suggest that dysbiosis and impaired intestinal barrier function may facilitate microbial-product translocation and lipopolysaccharide-mediated inflammatory signaling, while GV may contribute to oxidative stress, endothelial dysfunction, and pro-inflammatory responses. Mesenteric vascular anatomy and impaired regional perfusion may represent additional factors influencing local tissue susceptibility. Recent randomized controlled trials of microbiome-targeted interventions in metabolic disorders have shown heterogeneous effects on glycemic, inflammatory, and microbiota-related outcomes. Future investigation of individualized microbiome-directed strategies is needed. Recent evidence demonstrating that these microbial, metabolic, or vascular mechanisms initiate or sustain MP remains limited. The proposed gut–mesentery–metabolic axis should be regarded as a hypothesis for further investigation. Prospective studies integrating microbiome profiling, metabolic biomarkers, glycemic variability assessment, vascular evaluation, and imaging phenotypes are needed to clarify if biological subgroups of MP can be identified.