Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation.

In white adipose tissue, disturbed creatine metabolism through reduced creatine kinase B (CKB) transcription contributes to obesity-related inflammation. However, the mechanisms regulating CKB expression in human white adipocytes remain unclear. By screening conditions perturbed in obesity, we identified endoplasmic reticulum (ER) stress as a key suppressor of CKB transcription across multiple cell types.

Impaired branched-chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.

Dysregulated branched-chain amino acid (BCAA) metabolism has emerged as a key metabolic feature associated with the obese insulin-resistant state, and adipose BCAA catabolism is decreased in this context. BCAA catabolism is upregulated early in adipogenesis, but the impact of suppressing this pathway on the broader metabolic functions of the resultant adipocyte remains unclear. Here, we use CRISPR/Cas9 to decrease BCKDHA in 3T3-L1 and human pre-adipocytes, and ACAD8 in 3T3-L1 pre-adipocytes to induce a deficiency in BCAA catabolism through differentiation.

Weight Changes Are Linked to Adipose Tissue Genes in Overweight Women with Polycystic Ovary Syndrome.

Women with polycystic ovary syndrome (PCOS) have varying difficulties in achieving weight loss by lifestyle intervention, which may depend on adipose tissue metabolism. The objective was to study baseline subcutaneous adipose tissue gene expression as a prediction of weight loss by lifestyle intervention in obese/overweight women with PCOS. This is a secondary analysis of a randomized controlled trial where women with PCOS, aged 18-40 and body mass index (BMI) ≥ 27 were initially randomized to either a 4-month behavioral modification program or minimal intervention according to standard care.

Decreased mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin in type 2 diabetes.

Increased plasma creatine concentrations are associated with the risk of type 2 diabetes, but whether this alteration is associated with or causal for impairments in metabolism remains unexplored. Because skeletal muscle is the main disposal site of both creatine and glucose, we investigated the role of intramuscular creatine metabolism in the pathophysiology of insulin resistance in type 2 diabetes. In men with type 2 diabetes, plasma creatine concentrations were increased, and intramuscular phosphocreatine content was reduced.

Reduced adipocyte glutaminase activity promotes energy expenditure and metabolic health.

Glutamine and glutamate are interconverted by several enzymes and alterations in this metabolic cycle are linked to cardiometabolic traits. Herein, we show that obesity-associated insulin resistance is characterized by decreased plasma and white adipose tissue glutamine-to-glutamate ratios. We couple these stoichiometric changes to perturbed fat cell glutaminase and glutamine synthase messenger RNA and protein abundance, which together promote glutaminolysis.

Circadian transcriptome oscillations in human adipose tissue depend on napping status and link to metabolic and inflammatory pathways.

Study Objectives: Napping is a common habit in many countries. Nevertheless, studies about the chronic effects of napping on obesity are contradictory, and the molecular link between napping and metabolic alterations has yet to be studied. We aim to identify molecular mechanisms in adipose tissue (AT) that may connect napping and abdominal obesity.

The subcutaneous adipose transcriptome identifies a molecular signature of insulin resistance shared with visceral adipose.

Objective: The objective of this study was to identify the transcriptional landscape of insulin resistance (IR) in subcutaneous adipose tissue (SAT) in humans across the spectrum of obesity.

Methods: We used SAT RNA sequencing in 220 individuals with metabolic phenotyping.

Results: We identified a 35-gene signature with high predictive accuracy for homeostatic model of IR that was expressed across a variety of non-immune cell populations.

Exploring the Early Molecular Pathogenesis of Osteoarthritis Using Differential Network Analysis of Human Synovial Fluid.

The molecular mechanisms that drive the onset and development of osteoarthritis (OA) remain largely unknown. In this exploratory study, we used a proteomic platform (SOMAscan assay) to measure the relative abundance of more than 6000 proteins in synovial fluid (SF) from knees of human donors with healthy or mildly degenerated tissues, and knees with late-stage OA from patients undergoing knee replacement surgery. Using a linear mixed effects model, we estimated the differential abundance of 6251 proteins between the three groups.

Diagnostic challenges in patients with reninomas and extrarenal renin-producing tumours.

Renin-secreting tumours are rare causes of secondary hypertension and hypokalaemia. They are usually surgically curable, hence proper diagnostic work-up and tumour localisation is essential. In this paper, we present three Swedish patients recently diagnosed with renin secreting tumours, two with reninomas and one with an extrarenal renin-producing tumour, to illustrate diagnostic challenges.

A spatiotemporal proteomic map of human adipogenesis.

White adipocytes function as major energy reservoirs in humans by storing substantial amounts of triglycerides, and their dysfunction is associated with metabolic disorders; however, the mechanisms underlying cellular specialization during adipogenesis remain unknown. Here, we generate a spatiotemporal proteomic atlas of human adipogenesis, which elucidates cellular remodelling as well as the spatial reorganization of metabolic pathways to optimize cells for lipid accumulation and highlights the coordinated regulation of protein localization and abundance during adipocyte formation. We identify compartment-specific regulation of protein levels and localization changes of metabolic enzymes to reprogramme branched-chain amino acids and one-carbon metabolism to provide building blocks and reduction equivalents.

The expectations and experiences of patients regarding the diagnostic workup at a specialized memory clinic: An interview study.

Background: Because of the shift towards earlier diagnosis of dementia and/or Alzheimer's disease (AD), increasing numbers of individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) are seen in memory clinics. Yet, evidence indicates that there is room for improvement when it comes to tailoring of the diagnostic work-up to the needs of individual patients. To optimize the quality of care, we explored patients' perspectives regarding the diagnostic work-up at a specialized memory clinic.

P2Y13 receptor deficiency favors adipose tissue lipolysis and worsens insulin resistance and fatty liver disease.

Excessive lipolysis in white adipose tissue (WAT) leads to insulin resistance (IR) and ectopic fat accumulation in insulin-sensitive tissues. However, the impact of Gi-coupled receptors in restraining adipocyte lipolysis through inhibition of cAMP production remained poorly elucidated. Given that the Gi-coupled P2Y13 receptor (P2Y13-R) is a purinergic receptor expressed in WAT, we investigated its role in adipocyte lipolysis and its effect on IR and metabolic dysfunction-associated steatotic liver disease (MASLD).

Targeted Proteomics Reveals Functional Targets for Early Diabetes Susceptibility in Young Adults.

Background: The circulating proteome may encode early pathways of diabetes susceptibility in young adults for surveillance and intervention. Here, we define proteomic correlates of tissue phenotypes and diabetes in young adults.

Methods: We used penalized models and principal components analysis to generate parsimonious proteomic signatures of diabetes susceptibility based on phenotypes and on diabetes diagnosis across 184 proteins in >2000 young adults in the CARDIA (Coronary Artery Risk Development in Young Adults study; mean age, 32 years; 44% women; 43% Black; mean body mass index, 25.

Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation.

Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD.

Insulin resistance in adipocytes: Novel insights into the pathophysiology of metabolic syndrome.

Background: Insulin resistance in all major target tissues is present in metabolic syndrome (MetS). The resistance in adipocytes is not well described and was presently examined.

Methods: In this observational study on isolated abdominal white subcutaneous adipocytes from 419 adults, concentration-response effects of insulin on lipolysis inhibition (glycerol release) and lipogenesis stimulation (glucose conversion to total lipids) were determined.

Transcriptional determinants of lipid mobilization in human adipocytes.

Defects in adipocyte lipolysis drive multiple aspects of cardiometabolic disease, but the transcriptional framework controlling this process has not been established. To address this, we performed a targeted perturbation screen in primary human adipocytes. Our analyses identified 37 transcriptional regulators of lipid mobilization, which we classified as (i) transcription factors, (ii) histone chaperones, and (iii) mRNA processing proteins.

Exercise-induced crosstalk between immune cells and adipocytes in humans: Role of oncostatin-M.

The discovery of exercise-regulated circulatory factors has fueled interest in organ crosstalk, especially between skeletal muscle and adipose tissue, and the role in mediating beneficial effects of exercise. We studied the adipose tissue transcriptome in men and women with normal glucose tolerance or type 2 diabetes following an acute exercise bout, revealing substantial exercise- and time-dependent changes, with sustained increase in inflammatory genes in type 2 diabetes. We identify oncostatin-M as one of the most upregulated adipose-tissue-secreted factors post-exercise.

Adipogenic characterization of immortalized CD55 progenitor cells from human white adipose tissue.

Background: Mature adipocytes are notoriously difficult to study ex vivo and alternative cell culture systems have therefore been developed. One of the most common models are human adipose progenitor cells (hAPCs). Unfortunately, these display replicative senescence after prolonged culture conditions, which limits their use in mechanistic studies.

Association of Sarcopenia and Its Defining Components with the Degree of Cognitive Impairment in a Memory Clinic Population.

Background: Sarcopenia and cognitive impairment are two leading causes of disabilities.

Objective: The objective was to examine the prevalence of sarcopenia and investigate the association between sarcopenia diagnostic components (muscle strength, muscle mass, and physical performance) and cognitive impairment in memory clinic patients.

Methods: 368 patients were included (age 59.

CRISPR/Cas9-mediated deletion of adipocyte genes associated with NAFLD alters adipocyte lipid handling and reduces steatosis in hepatocytes in vitro.

Obesity is a major risk factor for the development of nonalcoholic fatty liver disease (NAFLD), and the subcutaneous white adipose tissue (scWAT) is the primary lipid storage depot and regulates lipid fluxes to other organs. Our previous work identified genes upregulated in scWAT of patients with NAFLD: , , and . Herein, we knocked down (KD) their expression in human adipose-derived mesenchymal stem cells (hADMSCs) using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology and characterized their phenotype.

Genetic Influence on Osteoarthritis Versus Other Rheumatic Diseases.

Objective: We aimed to compare the genetic contribution to osteoarthritis (OA) versus other rheumatic/musculoskeletal diseases (RMDs) in the same population and to explore the role for any shared genetics between OA and other RMDs.

Methods: In 59,970 Swedish twins aged 35 years or older, we estimated the heritability (the variance explained by genetic factors) of OA in peripheral joints, back and neck pain, shoulder pain (adhesive capsulitis, impingement syndrome, etc), rheumatoid arthritis, spondyloarthritis (SpA) and psoriatic arthritis, myalgia, and osteoporosis diagnosed in specialist and inpatient care. We also studied how much covariance between OA and each of the RMDs could be explained by genetics by studying phenotypic correlations in bivariate classical twin models.