Gabriella Milan

Background: Multiple symmetric lipomatosis (MSL) is an orphan disease characterized by pathological expansion of lipomatous tissue (LT) in the subcutaneous adipose tissue (SAT) areas, causing severe deformities and compression of vital organs. To date, the only treatment options available are either lifestyle modification or surgical excision/liposuction. Since sex hormones play an important role in adipose tissue (AT) expansion, they may represent an opportunity for pharmacological treatment. Methods: LT and control SAT were collected from eight MSL patients. Both tissues and derived stromal vascular fraction (SVF) were compared in terms of aromatase (hCYP19A1) and 5-α-reductase isoform (hSRD5A1, -2 and -3) mRNA expression. Primary cultures obtained from one MSL patient were exposed to an aromatase inhibitor, 5-α-reductase inhibitor and DL-α-Lipoic Acid and assayed for cell viability, proliferation and adipogenic differentiation. Results: hCYP19A1, hSRD5A1 and hSRD5A3 were expressed in both MSL-affected and MSL-spared tissues at different levels. Cell viability and proliferation of LT-derived SVF cells were slightly increased by treatment with DL-α-Lipoic Acid and the aromatase inhibitor. Adipogenesis was slightly reduced by Finasteride and strongly reduced by Exemestane (more in LT- than in SAT- derived primary cultures). Conclusions: These preliminary results pave the way for the use of aromatase and 5-α-reductase inhibition as a potential pharmacological approach to tackling dysfunctional adipogenesis in MSL. Therefore, the reported study should be interpreted as exploratory and further experiments are recommended in a larger number of patients to validate these promising results.

Background/Objectives: A disruption of eating habits is related to obesity and obesity-related complications (ORCs), including diabetes and cardiovascular disease. We previously described chrono-nutritional profiles considering the eating habits of patients with severe obesity during the 24 h cycle. Our present study aims to determine, first, whether belonging to a specific eating profile is associated with greater or lesser weight loss in patients with obesity who have undergone bariatric surgery, and second, whether chrono-nutritional profiles are associated with the remission of ORCs after surgery. We also investigated whether there were differences between the original baseline profile and the new profile derived from the 24 h recall on dietary patterns. Methods: The study included 75 patients with obesity who had undergone bariatric surgery and were followed up for a period of 36 ± 11 months. Data were collected from patients’ medical records and telephone interviews. R software (v4.4.0; R Core Team, 2024) was used. Results: Significant weight loss from baseline was observed at follow-up for all profiles (p < 0.0001); however, there were no significant differences in weight loss % among profiles. Using a linear regression model, Profile 3 (characterized by irregular eating patterns) demonstrated less weight loss at follow-up compared to other profiles (p = 0.0487). There was a significant remission of ORCs from baseline to follow-up, but there were no significant differences among profiles. Conclusions: Chrono-nutritional profiles may play a role in weight regulation in patients with severe obesity who are candidates for bariatric surgery. Further studies with a larger sample size are needed.

Adipose tissue (AT) is composed of a heterogeneous population which comprises both progenitor and differentiated cells. This heterogeneity allows a variety of roles for the AT, including regenerative functions. In fact, autologous AT is commonly used to repair soft tissue defects, and its cryopreservation could be a useful strategy to reduce the patient discomfort caused by multiple harvesting procedures. Our work aimed to characterize the cryopreserved AT and to validate its storage for up to three years for clinical applications. AT components (stromal vascular fraction-SVF and mature adipocytes) were isolated in fresh and cryopreserved samples using enzymatic digestion, and cell viability was assessed by immunofluorescence (IF) staining. Live, apoptotic and necrotic cells were quantified using cytometry by evaluating phosphatidylserine binding to fluorescent-labeled Annexin V. A multiparametric cytometry was also used to measure adipogenic (CD34+CD90+CD31−CD45−) and endothelial (CD34+CD31+CD45−) precursors and endothelial mature cells (CD34−CD31+CD45−). The maintenance of adipogenic abilities was evaluated using in vitro differentiation of SVF cultures and fluorescent lipid staining. We demonstrated that AT that is cryopreserved for up to three years maintains its differentiation potential and cellular composition. Given our results, a clinical study was started, and two patients had successful transplants without any complications using autologous cryopreserved AT.

Epidemiological observations, experimental studies and clinical data show that obesity is associated with a higher risk of developing different types of cancer; however, proof of a cause–effect relationship that meets the causality criteria is still lacking. Several data suggest that the adipose organ could be the protagonist in this crosstalk. In particular, the adipose tissue (AT) alterations occurring in obesity parallel some tumour behaviours, such as their theoretically unlimited expandability, infiltration capacity, angiogenesis regulation, local and systemic inflammation and changes to the immunometabolism and secretome. Moreover, AT and cancer share similar morpho-functional units which regulate tissue expansion: the adiponiche and tumour-niche, respectively. Through direct and indirect interactions involving different cellular types and molecular mechanisms, the obesity-altered adiponiche contributes to cancer development, progression, metastasis and chemoresistance. Moreover, modifications to the gut microbiome and circadian rhythm disruption also play important roles. Clinical studies clearly demonstrate that weight loss is associated with a decreased risk of developing obesity-related cancers, matching the reverse-causality criteria and providing a causality correlation between the two variables. Here, we provide an overview of the methodological, epidemiological and pathophysiological aspects, with a special focus on clinical implications for cancer risk and prognosis and potential therapeutic interventions.

White to brown/beige adipocytes conversion is a possible therapeutic strategy to tackle the current obesity epidemics. While mitochondria are key for energy dissipation in brown fat, it is unknown if they can drive adipocyte browning. Here, we show that the mitochondrial cristae biogenesis protein optic atrophy 1 (Opa1) facilitates cell-autonomous adipocyte browning. In two cohorts of patients with obesity, including weight discordant monozygotic twin pairs, adipose tissue OPA1 levels are reduced. In the mouse, Opa1 overexpression favours white adipose tissue expandability as well as browning, ultimately improving glucose tolerance and insulin sensitivity. Transcriptomics and metabolomics analyses identify the Jumanji family chromatin remodelling protein Kdm3a and urea cycle metabolites, including fumarate, as effectors of Opa1-dependent browning. Mechanistically, the higher cyclic adenosine monophosphate (cAMP) levels in Opa1 pre-adipocytes activate cAMP-responsive element binding protein (CREB), which transcribes urea cycle enzymes. Flux analyses in pre-adipocytes indicate that Opa1-dependent fumarate accumulation depends on the urea cycle. Conversely, adipocyte-specific Opa1 deletion curtails urea cycle and beige differentiation of pre-adipocytes, and is rescued by fumarate supplementation. Thus, the urea cycle links the mitochondrial dynamics protein Opa1 to white adipocyte browning.

In physiological conditions, the adipose organ resides in well-defined areas, where it acts providing an energy supply and as an endocrine organ involved in the control of whole-body energy metabolism. Adipose tissue adipokines connect the body’s nutritional status to the regulation of energy balance. When it surrounds organs, it provides also for mechanical protection. Adipose tissue has a complex and heterogenous cellular composition that includes adipocytes, adipose tissue-derived stromal and stem cells (ASCs) which are mesenchymal stromal cells, and endothelial and immune cells, which signal to each other and to other tissues to maintain homeostasis. In obesity and in other nutrition related diseases, as well as in age-related diseases, biological and functional changes of adipose tissue give rise to several complications. Obesity triggers alterations of ASCs, impairing adipose tissue remodeling and adipose tissue function, which induces low-grade systemic inflammation, progressive insulin resistance and other metabolic disorders. Adipose tissue grows by hyperplasia recruiting new ASCs and by hypertrophy, up to its expandability limit. To overcome this limitation and to store the excess of nutrients, adipose tissue develops ectopically, involving organs such as muscle, bone marrow and the heart. The origin of ectopic adipose organ is not clearly elucidated, and a possible explanation lies in the stimulation of the adipogenic differentiation of mesenchymal precursor cells which normally differentiate toward a lineage specific for the organ in which they reside. The chronic exposition of these newly-formed adipose depots to the pathological environment, will confer to them all the phenotypic characteristics of a dysfunctional adipose tissue, perpetuating the organ alterations. Visceral fat, but also ectopic fat, either in the liver, muscle or heart, can increase the risk of developing insulin resistance, type 2 diabetes, and cardiovascular diseases. Being able to prevent and to target dysfunctional adipose tissue will avoid the progression towards the complications of obesity and other nutrition-related diseases. The aim of this review is to summarize some of the knowledge regarding the presence of adipose tissue in particular tissues (where it is not usually present), describing the composition of its adipogenic precursors, and the interactions responsible for the development of organ pathologies.

Background/Objectives Different approaches are used to classify obesity severity. Beyond classical anthropometric measurements, the Edmonton Obesity Staging System (EOSS) considers medical, physical and psychological parameters. However, this method has some limitations, principally due to the absence of an objective measure for physical impairment. The aim of our study is thus to overcome this limitation suggesting a new functional parameter obtained by cardiopulmonary exercise testing (CPET), i.e., cardiorespiratory fitness (CRF), expressed as weight-adjusted peak oxygen consumption (VO₂peak/kg). Subjects/Methods This observational cross-sectional study conducted on a population of 843 patients affected by obesity finally enrolled 500 subjects. Every patient underwent clinical, anthropometric, biochemical assessment and CPET. First, participants have been classified according to standard EOSS in five stages. Second, patients were reclassified according to the new modified EOSS (EOSS-CRF) based on their age- and gender-appropriate VO₂peak/kg percentiles as reported in the healthy normal-weight population of the FRIEND registry. Results VO₂peak/kg was significantly different between standard EOSS classes 1 and 2 and classes 1 and 3 (ANCOVA p model = 0.004), whereas patients in classes 2 and 3 showed similar CRF. The EOSS-CRF classification varied in number of patients in each class compared to EOSS, particularly with a shift from class 2 to class 3. Moreover, CRF showed that physical impairment is less addressed by EOSS when compared to EOSS-CRF. Conclusions The integration of EOSS with CRF allowed us to assign to each patient a severity index that considers not only clinical parameters, but also their functional impairment through a quantitative and prognostically important parameter (VO₂peak/kg). This improvement of the staging system may also provide a better approach to identify individuals at increased risk of mortality leading to targeted therapeutic management and prognostic risk stratification for patients with obesity.