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Obesity is a major health risk factor, and obesity-induced morbidity and complications account for huge costs for affected individuals, families, healthcare systems, and society at large. In particular, obesity is strongly associated with the development of insulin resistance, which in turn plays a key role in the pathogenesis of obesity-associated cardiometabolic complications, including metabolic syndrome components, type 2 diabetes, and cardiovascular diseases. Insulin sensitive tissues, including adipose tissue, skeletal muscle, and liver, are profoundly affected by obesity both at biomolecular and functional levels. Altered adipose organ function may play a fundamental pathogenetic role once fat accumulation has ensued. Modulation of insulin sensitivity appears to be, at least in part, related to changes in redox balance and oxidative stress as well as inflammation, with a relevant underlying role for mitochondrial dysfunction that may exacerbate these alterations. Nutrients and substrates as well as systems involved in host–nutrient interactions, including gut microbiota, have been also identified as modulators of metabolic pathways controlling insulin action. This review aims at providing an overview of these concepts and their potential inter-relationships in the development of insulin resistance, with particular regard to changes in adipose organ and skeletal muscle.

Musculoskeletal pain conditions are age-related, leading contributors to chronic pain and pain-related disability, which are expected to rise with the rapid global population aging. Current medical treatments provide only partial relief. Furthermore, non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are effective in young and otherwise healthy individuals but are often contraindicated in elderly and frail patients. As a result of its favorable safety and tolerability record, paracetamol has long been the most common drug for treating pain. Strikingly, recent reports questioned its therapeutic value and safety. This review aims to present guideline recommendations. Paracetamol has been assessed in different conditions and demonstrated therapeutic efficacy on both acute and chronic pain. It is active as a single agent and is additive or synergistic with NSAIDs and opioids, improving their efficacy and safety. However, a lack of significant efficacy and hepatic toxicity have also been reported. Fast dissolving formulations of paracetamol provide superior and more extended pain relief that is similar to intravenous paracetamol. A dose reduction is recommended in patients with liver disease or malnourished. Genotyping may improve efficacy and safety. Within the current trend toward the minimization of opioid analgesia, it is consistently included in multimodal, non-opioid, or opioid-sparing therapies. Paracetamol is being recommended by guidelines as a first or second-line drug for acute pain and chronic pain, especially for patients with limited therapeutic options and for the elderly.

As the number of confirmed cases of COVID-19 surges past 4.7 million globally and deaths surpass 315,000, clinicians and pathologists are untiringly working to comprehend the damage produced by the coronavirus through the body. They are understanding that, yet the lungs are massively deranged, COVID-19 infection can outspread to many organs including the blood vessels and heart, gut, brain, and kidneys [1]. A systemic therapeutic approach is necessary; we thus analyzed a global interpretation of multi-organ symptoms and signs to propose a new pathogenetic hypothesis, with potential drug therapy implications, in COVID-19 people with obesity.

Rapid tumor growth requires elevated biosynthetic activity, supported by metabolic rewiring occurring both intrinsically in cancer cells and extrinsically in the cancer host. The Warburg effect is one such example, burning glucose to produce a continuous flux of biomass substrates in cancer cells at the cost of energy wasting metabolic cycles in the host to maintain stable glycemia. Amino acid (AA) metabolism is profoundly altered in cancer cells, which use AAs for energy production and for supporting cell proliferation. The peculiarities in cancer AA metabolism allow the identification of specific vulnerabilities as targets of anti-cancer treatments. In the current review, specific approaches targeting AAs in terms of either deprivation or supplementation are discussed. Although based on opposed strategies, both show, in vitro and in vivo, positive effects. Any AA-targeted intervention will inevitably impact the cancer host, who frequently already has cachexia. Cancer cachexia is a wasting syndrome, also due to malnutrition, that compromises the effectiveness of anti-cancer drugs and eventually causes the patient’s death. AA deprivation may exacerbate malnutrition and cachexia, while AA supplementation may improve the nutritional status, counteract cachexia, and predispose the patient to a more effective anti-cancer treatment. Here is provided an attempt to describe the AA-based therapeutic approaches that integrate currently distant points of view on cancer-centered and host-centered research, providing a glimpse of several potential investigations that approach cachexia as a unique cancer disease.

Since the outbreak of COVID-19, clinicians have tried every effort to fight the disease, and multiple drugs have been proposed. However, no proven effective therapies currently exist, and different clinical phenotypes complicate the situation. In clinical practice, many severe or critically ill COVID-19 patients developed gastrointestinal (GI) disturbances, including vomiting, diarrhoea, or abdominal pain, even in the absence of cough and dyspnea. Understanding the mechanism of GI disturbances is warranted for exploring better clinical care for COVID-19 patients. With evidence collected from clinical studies on COVID-19 and basic research on a rare genetic disease (i.e., Hartnup disorder), we put forward a novel hypothesis to elaborate an effective nutritional therapy. We hypothesize that SARS-CoV-2 spike protein, binding to intestinal angiotensin-converting enzyme 2, negatively regulates the absorption of neutral amino acids, and this could explain not only the GI, but also systemic disturbances in COVID-19. Amino acid supplements could be recommended. Level of evidence No level of evidence: Hypothesis article.

Dietary restriction (DR) has long been recognized as a powerful intervention for extending lifespan and improving metabolic health across species. In laboratory animals, DR—typically a 30%–40% reduction in caloric intake—delays aging and enhances mitochondrial function, oxidative defense, and anti-inflammatory pathways. In humans, findings from the CALERIE™ trial confirm DR’s potential benefits, with a 25% caloric reduction over 2 years resulting in reduced visceral fat, improved cardiometabolic health, and favorable gene expression changes linked to proteostasis, DNA repair, and inflammation. However, recent research in genetically diverse mouse populations reveals that the impact of DR on lifespan is substantially modulated by genetic background, underscoring the importance of individual variability. Additionally, emerging evidence challenges previous assumptions that lower body temperature universally benefits lifespan extension, with data indicating complex relationships between thermoregulation, sex, and longevity. These findings underscore the need for nuanced approaches to DR in both research and potential therapeutic applications, with considerations for genetic and sex-specific factors to maximize healthspan and lifespan outcomes.

[...]long-term obesity has been associated with the expression of molecular ageing signatures during young adulthood in both females and males, reinforcing the view that obesity may constitute a state of accelerated biological ageing (Correa-Burrows et al., 2025). In this context, the chronic consumption of a Western diet rich in processed foods, sugars, and unhealthy fats promotes chronic inflammation in multiple organs (Clemente-Suárez et al., 2023), driving adipose tissue expansion and dysfunction, factors that The Lancet Commission identified as key determinants of the clinical manifestations of obesity (Rubino et al., 2025). (2025)show that ginger supplementation, whose antioxidant activity derives largely from its phenolic compounds, counteracts age-related oxidative stress in the mouse liver, restoring antioxidant capacity in a dose- and ageing-dependent manner. [...]targeting senescence has emerged as a promising strategy to counteract these processes and improve metabolic health (Childs et al., 2015;Zumerle et al., 2024).

Dysregulated adipocyte physiology leads to imbalanced energy storage, obesity, and associated diseases, imposing a costly burden on current health care. Cannabinoid receptor type-1 (CB1) plays a crucial role in controlling energy metabolism through central and peripheral mechanisms. In this work, adipocyte-specific inducible deletion of the CB1 gene (Ati-CB1-KO) was sufficient to protect adult mice from diet-induced obesity and associated metabolic alterations and to reverse the phenotype in already obese mice. Compared with controls, Ati-CB1-KO mice showed decreased body weight, reduced total adiposity, improved insulin sensitivity, enhanced energy expenditure, and fat depot-specific cellular remodeling toward lowered energy storage capacity and browning of white adipocytes. These changes were associated with an increase in alternatively activated macrophages concomitant with enhanced sympathetic tone in adipose tissue. Remarkably, these alterations preceded the appearance of differences in body weight, highlighting the causal relation between the loss of CB1 and the triggering of metabolic reprogramming in adipose tissues. Finally, the lean phenotype of Ati-CB1-KO mice and the increase in alternatively activated macrophages in adipose tissue were also present at thermoneutral conditions. Our data provide compelling evidence for a crosstalk among adipocytes, immune cells, and the sympathetic nervous system (SNS), wherein CB1 plays a key regulatory role.

BackgroundPreliminary data suggested that fat embolism could explain the importance of visceral obesity as a critical determinant of coronavirus disease-2019 (COVID-19).MethodsWe performed a comprehensive histomorphologic analysis of autoptic visceral adipose tissue (VAT), lungs and livers of 19 subjects with COVID-19 (COVID-19+), and 23 people without COVID-19 (controls). Human adipocytes (hMADS) infected with SARS-CoV-2 were also studied.ResultsAlthough there were no between-group differences in body-mass-index and adipocytes size, a higher prevalence of CD68+ macrophages among COVID-19+ VAT was detected (p = 0.005) and accompanied by crown-like structures presence, signs of adipocytes stress and death. Consistently, human adipocytes were successfully infected by SARS-CoV-2 in vitro and displayed lower cell viability. Being VAT inflammation associated with lipids spill-over from dead adipocytes, we studied lipids distribution by ORO. Lipids were observed within lungs and livers interstitial spaces, macrophages, endothelial cells, and vessels lumen, features suggestive of fat embolism syndrome, more prevalent among COVID-19+ (p < 0.001). Notably, signs of fat embolism were more prevalent among people with obesity (p = 0.03) independently of COVID-19 diagnosis, suggesting that such condition may be an obesity complication exacerbated by SARS-CoV-2 infection. Importantly, all infected subjects’ lungs presented lipids-rich (ORO+) hyaline membranes, formations associated with COVID-19-related pneumonia, present only in one control patient with non-COVID-19-related pneumonia. Importantly, transition aspects between embolic fat and hyaline membranes were also observed.ConclusionsThis study confirms the lung fat embolism in COVID-19+ patients and describes for the first time novel COVID-19-related features possibly underlying the unfavorable prognosis in people with COVID-19 and obesity.

Mitochondria play a central role in regulating cellular energy metabolism, redox homeostasis, and biosynthesis. Mitochondrial uncoupling, through the alteration in the permeability of the inner mitochondrial membrane (IMM) to the leak of protons without adenosine triphosphate (ATP) synthesis, regulates thermogenesis, glucose and lipid metabolism, and reactive oxygen species (ROS) generation. In brown adipose tissue (BAT), proton leak via uncoupling protein 1 (UCP1) is essential for thermogenesis and has been shown to improve systemic glucose homeostasis, and recent studies indicate that BAT activation can also suppress tumor growth by competing with cancer cells for glucose. Several small-molecule mitochondrial uncouplers have demonstrated anticancer effects in preclinical models, although endogenous UCPs—particularly UCP2—are often upregulated in tumors, where they may support tumor growth by buffering ROS and increasing metabolic flexibility. These seemingly contradictory observations highlight the context-dependent effects of mitochondrial uncoupling in cancer. Here, we review current understanding of mitochondrial uncoupling mechanisms, the roles of UCP isoforms, and the metabolic interplay between BAT, cancer cells, and the tumor microenvironment, with a focus on therapeutic implications.