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Chronic kidney disease (CKD) and heart diseases (cardiovascular disease, atherosclerotic heart disease, heart failure) and metabolic diseases (metabolic syndrome [MetS], type 2 diabetes [T2DM], hyperuricemia) often occur together. The common, initiating risk factor for these diseases is visceral obesity/dysfunctional adipose tissue and the associated dyslipidemia (elevated triglycerides, reduced HDL, small high-density LDL cholesterol), high blood pressure, smoking and inflammatory phenomena, as well as insulin resistance. This disease combination can often lead to an unfavorable clinical outcome in detail and overall. The working group of the American Heart Association (AHA) called this combination of diseases cardio-renal-metabolic syndrome (CRMS), and classified it according to progression. The pathomechanism of the syndrome is complex, centered on visceral dysfunctional fat tissue. Using large clinical databases, a new type of 10- and 30-year cardiovascular (CV) risk estimation model was developed based on the characteristics of individual CRMS components.

The Dysfunctional Adiposity Index (DAI) is a clinical surrogate for evaluating adipose tissue functionality and cardiometabolic health. However, its association with Pericardial Fat Volume (PFV) has not been tested. The aim of this study was to evaluate DAI- PFV association, stratified by type 2 diabetes (T2D) status, and identify DAI thresholds for detecting increased PFV among patients without premature CVD. Participants from the GEA-Mexican study underwent a computed tomography scan to measure PFV. Adjusted logistic regression analyses tested the association between DAI and PFV. AUROC curves evaluated DAI's ability to identify elevated PFV (≥57.57 cm³), and the Youden method determined DAI thresholds, along with diagnostic metrics. The study analyzed 997 participants (women: 55%; mean age: 54 ± 9 years; median PFV: 42 cm³ [IQR: 29–58]), with a 13% prevalence of T2D. DAI was positively associated with elevated PFV (OR: 1.33, 95% CI: 1.07–1.70), which was more pronounced among subjects with T2D (OR: 3.01, 95% CI: 1.41–6.40). DAI thresholds were established for all participants (>1.176), individuals without T2D (>1.003), and with T2D (>1.936), yielding sensitivities of 71%, 81%, and 57%, and specificities of 48%, 38%, and 75%, respectively. The adjusted logistic regression tied DAI thresholds to a 1.68-fold elevation in PFV for all, 2.06-fold for those without T2D, and 6.81-fold for those with T2D. DAI was positively associated with increased PFV, particularly among participants with T2D. Established DAI thresholds demonstrated good diagnostic values for detecting increased PFV. DAI could serve as an accessible marker to identify PF in clinical settings. • DAI predicts pericardial fat in the GEA study. • Strong DAI-pericardial fat association in T2D. • DAI >1.936 identifies elevated pericardial fat. • DAI could be a tool for cardiometabolic health assessment. • DAI as a marker for increased pericardial fat. [ABSTRACT FROM AUTHOR]

We are entering a new era in the management of adiposity-based chronic disease (ABCD) with type 2 diabetes (T2D) and related chronic kidney disease (CKD). ABCD, T2D and CKD can affect almost every major organ system and have a particularly strong impact on the incidence of cardiovascular disease (CVD) and heart failure. ABCD and the associated insulin resistance are at the root of many cardiovascular, renal and metabolic (CKM) disorders, thus an integrated therapeutic framework using weight loss (WL) as a disease-modifying intervention could simplify the therapeutic approach at different stages across the lifespan. The breakthrough of highly effective WL drugs makes achieving a WL of >10% possible, which is required for a potential T2D disease remission as well as for prevention of microvascular disease, CKD, CVD events and overall mortality. The aim of this review is to discuss the link between adiposity and CKM conditions as well as placing weight management at the centre of the holistic CKM syndrome approach with a focus on CKD. We propose the clinical translation of the available evidence into a transformative Dysfunctional Adipose Tissue Approach (DATA) for people living with ABCD, T2D and CKD. This model is based on the interplay of four essential elements (i.e. adipocentric approach and target organ protection, dysfunctional adiposity, glucose homeostasis, and lifestyle intervention and de-prescription) together with a multidisciplinary person-centred care. DATA could facilitate decision-making for all clinicians involved in the management of these individuals, and if we do this in a multidisciplinary way, we are prepared to meet the adipocentric challenge. [ABSTRACT FROM AUTHOR]

Academic medicine fosters research that moves from discovery to translation, at the same time as promoting education of the next generation of professionals.In the field of obesity, the supposed integration of knowledge, discovery and translation research to clinical care is being particularly hampered.The classification of obesity based on the body mass index does not account for several subtypes of obesity.The lack of a universally shared definition of "obesities" makes it impossible to establish the real burden of the different obesity phenotypes.The individual's genotype, adipotype, enterotype and microbiota interplays with macronutrient intake, appetite, metabolism and thermogenesis.Further investigations based on the concept of differently diagnosed "obesities" are required. [ABSTRACT FROM AUTHOR]

Objective: White adipose tissue (WAT) possesses the remarkable remodeling capacity, and maladaptation of this ability contributes to the development of obesity and associated comorbidities. Calsyntenin-3 (CLSTN3) is a transmembrane protein that promotes synapse development in brain. Even though this gene has been reported to be associated with adipose tissue, its role in the regulation of WAT function is unknown yet. We aim to further assess the expression pattern of CLSTN3 gene in human adipose tissue, and investigate its regulatory impact on WAT function. Methods: In our study, we observed the expression pattern of Clstn3/CLSTN3 gene in mouse and human WAT. Genetic association study and expression quantitative trait loci analysis were combined to identify the phenotypic effect of CLSTN3 gene variant in humans. This was followed by mouse experiments using adeno-associated virus-mediated human CLSTN3 overexpression in inguinal WAT. We investigated the effect of CLSTN3 on WAT function and overall metabolic homeostasis, as well as the possible underlying molecular mechanism. Results: We observed that CLSTN3 gene was routinely expressed in human WAT and predominantly enriched in adipocyte fraction. Furthermore, we identified that the variant rs7296261 in the CLSTN3 locus was associated with a high risk of obesity, and its risk allele was linked to an increase in CLSTN3 expression in human WAT. Overexpression of CLSTN3 in inguinal WAT of mice resulted in diet-induced local dysfunctional expansion, liver steatosis, and systemic metabolic deficiency. In vivo and ex vivo lipolysis assays demonstrated that CLSTN3 overexpression attenuated catecholamine-stimulated lipolysis. Mechanistically, CLSTN3 could interact with amyloid precursor protein (APP) in WAT and increase APP accumulation in mitochondria, which in turn impaired adipose mitochondrial function and promoted obesity. Conclusion: Taken together, we provide the evidence for a novel role of CLSTN3 in modulating WAT function, thereby reinforcing the fact that targeting CLSTN3 may be a potential approach for the treatment of obesity and associated metabolic diseases.

Obesity is a frequent, serious, complex, relapsing, and chronic disease process that represents a major public health problem. The coining of obesity as an adiposity-based chronic disease (ABCD) is of particular relevance being in line with EASO’s proposal to improve the International Classification of Diseases ICD-11 diagnostic criteria for obesity based on three dimensions, namely etiology, degree of adiposity, and health risks. The body mass index as a unique measurement of obesity does not reflect the whole complexity of the disease. Obesity complications are mainly determined by 2 pathological processes, i.e., physical forces (fat mass disease) as well as endocrine and immune responses (sick fat disease), which are embedded in a cultural and physical context leading to a specific ABCD stage.

Obesity is well‐known as the second factor for tumorigenesis after smoking and is bound up with the malignant progression of several kinds of cancers, including esophageal cancer, liver cancer, colorectal cancer, kidney cancer, and ovarian cancer. The increased morbidity and mortality of obesity‐related cancer are mostly attributed to dysfunctional adipose tissue. The possible mechanisms connecting dysfunctional adipose tissue to high cancer risk mainly focus on chronic inflammation, obesity‐related microenvironment, adipokine secretion disorder, and browning of adipose tissue, and so forth. The stromal vascular cells in adipose tissue trigger chronic inflammation through secreting inflammatory factors and promote cancer cell proliferation. Hypertrophic adipose tissues lead to metabolic disorders of adipocytes, such as abnormal levels of adipokines that mediate cancer progression and metastasis. Cancer patients often show adipose tissue browning and cancerous cachexia in an advanced stage, which lead to unsatisfied chemotherapy effect and poor prognosis. However, increasing evidence has shown that adipose tissue may display quite opposite effects in cancer development. Therefore, the interaction between cancers and adipose tissue exert a vital role in mediates adipose tissue dysfunction and further leads to cancer progression. In conclusion, targeting the dysfunction of adipose tissue provides a promising strategy for cancer prevention and therapy. [ABSTRACT FROM AUTHOR]

Obesity is a frequent, serious, complex, relapsing, and chronic disease process that represents a major public health problem. The coining of obesity as an adiposity-based chronic disease (ABCD) is of particular relevance being in line with EASO's proposal to improve the International Classification of Diseases ICD-11 diagnostic criteria for obesity based on three dimensions, namely etiology, degree of adiposity, and health risks. The body mass index as a unique measurement of obesity does not reflect the whole complexity of the disease. Obesity complications are mainly determined by 2 pathological processes, i.e., physical forces (fat mass disease) as well as endocrine and immune responses (sick fat disease), which are embedded in a cultural and physical context leading to a specific ABCD stage. [ABSTRACT FROM AUTHOR]

Obesity, a pandemic disease, is caused by an excessive accumulation of fat that can have detrimental effects on health. Adipose tissue plays a very important endocrine role, secreting different molecules that affect body physiology. In obesity, this function is altered, leading to a dysfunctional production of several factors, known as adipocytokines. This process has been linked to various comorbidities associated with obesity, such as carcinogenesis. In fact, several classical adipocytokines with increased levels in obesity have been demonstrated to exert a pro-carcinogenic role, including leptin, TNF-α, IL-6 and resistin, whereas others like adiponectin, with decreased levels in obesity, might have an anti-carcinogenic function. In this expanding field, new proteomic techniques and approaches have allowed the identification of novel adipocytokines, a number of which exhibit an altered production in obesity and type 2 diabetes and thus are related to adiposity. Many of these novel adipocytokines have also been identified in various tumour types, such as that of the breast, liver or endometrium, thereby increasing the list of potential contributors to carcinogenesis. This review is focused on the regulation of these novel adipocytokines by obesity, including apelin, endotrophin, FABP4, lipocalin 2, omentin-1, visfatin, chemerin, ANGPTL2 or osteopontin, emphasizing its involvement in tumorigenesis. [ABSTRACT FROM AUTHOR]

The aim of this work was to determine the effect of a fructose rich diet (FRD) consumed by the pregnant mother on the endocrine-metabolic and in vivo and in vitro adipose tissue (AT) functions of the male offspring in adulthood. At 60 days of age, rats born to FRD-fed mothers (F) showed impaired glucose tolerance after glucose overload and high circulating levels of leptin (LEP). Despite the diminished mass of retroperitoneal AT, this tissue was characterized by enhanced LEP gene expression, and hypertrophic adipocytes secreting in vitro larger amounts of LEP. Analyses of stromal vascular fraction composition by flow cytometry revealed a reduced number of adipocyte precursor cells. Additionally, 60 day-old control (C) and F male rats were subjected to control diet (CC and FC animals) or FRD (CF and FF rats) for three weeks. FF animals were heavier and consumed more calories. Their metabolic-endocrine parameters were aggravated; they developed severe hyperglycemia, hypertriglyceridemia, hyperleptinemia and augmented AT mass with hypertrophic adipocytes. Our study highlights that manipulation of maternal diet induced an offspring phenotype mainly imprinted with a severely unhealthy adipogenic process with undesirable endocrine-metabolic consequences, putting them at high risk for developing a diabetic state. [ABSTRACT FROM AUTHOR]

Vitamin D deficiency and dysfunctional adipose tissue are involved in the development of cardiometabolic disturbances (eg, hypertension, insulin resistance, type 2 diabetes mellitus, obesity, and dyslipidemia). We evaluated the relation between vitamin D and adipocytokines derived from adipose tissue. We studied 50 obese individuals who were classified into different subgroups according to medians of observed anthropometric parameters (body mass index, body fat percentage, waist circumference, and trunk fat mass). There was a negative correlation between vitamin D level and leptin and resistin (r = −.61, P < .01), while a positive association with adiponectin concentrations was found (r = .7, P < .001). Trend estimation showed that increase in vitamin D level is accompanied by intensive increase in adiponectin concentrations (growth coefficient: 12.13). In conclusion, a positive trend was established between vitamin D and the protective adipocytokine adiponectin. The clinical relevance of this relationship needs to be investigated in larger studies. [ABSTRACT FROM AUTHOR]

Background The combination of obesity and hypertension (HT) places patients at a higher risk for adverse cardiovascular outcomes and raises the need to establish the pathogenic mechanisms of this relationship. The aim of this study was to assess the effects of important weight loss on longitudinal changes in blood pressure (BP) and investigate the pathogenic factors associated with these changes. Methods We performed a prospective, open-label study including 37 obese hypertensive patients (28 females, mean age 52±8 yr) undergoing BS. Before BS, and at 4 and 12 months postoperatively, the body mass index (BMI), 24-h ambulatory BP, renin-angiotensin-aldosterone system (RAAS: plasma rennin activity, aldosterone, angiotensin II, and angiotensin converting enzyme), sympathetic nervous system (SNS: metanephrines, normetanephrines, and norepinephrine) components, leptin, insulin, and abdominal fat were measured. Results Before BS, HT-duration was 6±6 years, the BMI 45±5 kg/m 2 and excess weight (EBW) was 53±12 kg. At 12 months, the excess BMI loss was 14 kg/m 2 and the EBW loss was 70 %; HT remission was observed in 70%; 24-h (systolic 19±13/diastolic 7±9 mm Hg), day and night BP levels and aldosterone, norepinephrine, leptin, insulin, subcutaneous and visceral abdominal fat (VAT) significantly decreased ( P <.05). Mixed models for repeated measures revealed that HT-duration, baseline BP, BMI, and VAT area were the main variables associated with longitudinal changes in BP. Conclusion These results demonstrate that the hypotensive response after weight loss in severely hypertensive obese patients is mainly regulated by HT-duration, baseline BP, BMI and VAT area, independently of suppression of hyperinsulinemia or changes in RAAS and SNS components. [ABSTRACT FROM AUTHOR]

White adipose tissue (WAT) possesses the remarkable remodeling capacity, and maladaptation of this ability contributes to the development of obesity and associated comorbidities. Calsyntenin-3 (CLSTN3) is a transmembrane protein that promotes synapse development in brain. Even though this gene has been reported to be associated with adipose tissue, its role in the regulation of WAT function is unknown yet. We aim to further assess the expression pattern of CLSTN3 gene in human adipose tissue, and investigate its regulatory impact on WAT function. In our study, we observed the expression pattern of Clstn3 / CLSTN3 gene in mouse and human WAT. Genetic association study and expression quantitative trait loci analysis were combined to identify the phenotypic effect of CLSTN3 gene variant in humans. This was followed by mouse experiments using adeno-associated virus-mediated human CLSTN3 overexpression in inguinal WAT. We investigated the effect of CLSTN3 on WAT function and overall metabolic homeostasis, as well as the possible underlying molecular mechanism. We observed that CLSTN3 gene was routinely expressed in human WAT and predominantly enriched in adipocyte fraction. Furthermore, we identified that the variant rs7296261 in the CLSTN3 locus was associated with a high risk of obesity, and its risk allele was linked to an increase in CLSTN3 expression in human WAT. Overexpression of CLSTN3 in inguinal WAT of mice resulted in diet-induced local dysfunctional expansion, liver steatosis, and systemic metabolic deficiency. In vivo and ex vivo lipolysis assays demonstrated that CLSTN3 overexpression attenuated catecholamine-stimulated lipolysis. Mechanistically, CLSTN3 could interact with amyloid precursor protein (APP) in WAT and increase APP accumulation in mitochondria, which in turn impaired adipose mitochondrial function and promoted obesity. Taken together, we provide the evidence for a novel role of CLSTN3 in modulating WAT function, thereby reinforcing the fact that targeting CLSTN3 may be a potential approach for the treatment of obesity and associated metabolic diseases. • CLSTN3 is expressed in the adipocyte fraction of human adipose tissue and mainly localizes to the plasma membrane. • SNP rs7296261 in human CLSTN3 locus is associated with obesity risk. • Overexpression of CLSTN3 leads to adipose tissue dysfunction in mice. • CLSTN3 can attenuate catecholamine-stimulated lipolysis. • CLSTN3 overexpression increases mitochondrial APP localization of mouse adipose tissue. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that might affect up to one-third of the adult population in industrialised countries. NAFLD incorporates histologically and clinically different non-alcoholic entities; fatty liver (NAFL, steatosis hepatis) and steatohepatitis (NASH-characterised by hepatocyte ballooning and lobular inflammation ± fibrosis) might progress to cirrhosis and rarely to hepatocellular cancer. NAFL increasingly affects children (paediatric prevalence is 4.2%-9.6%). Type 2 diabetes mellitus (T2DM), insulin resistance (IR), obesity, metabolic syndrome and NAFLD are particularly closely related. Increased hepatic lipid storage is an early abnormality in insulin resistant women with a history of gestational diabetes mellitus. The accumulation of triacylglycerols in hepatocytes is predominantly derived from the plasma nonesterified fatty acid pool supplied largely by the adipose tissue. A few NAFLD susceptibility gene variants are associated with progressive liver disease, IR, T2DM and a higher risk for hepatocellular carcinoma. Although not approved, pharmacological approaches might be considered in NASH patients.