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.

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.

Adipose Insulin Resistance Associates With Dyslipidemia Independent of Liver Resistance and Involves Early Hormone Signaling.

Background: Adipose tissue insulin resistance is linked to altered plasma levels of triglycerides and HDL (high-density lipoprotein)-cholesterol. However, its degree of independence from liver resistance and different metabolic traits (lipolysis, lipogenesis) effected is not clear and was presently investigated.

Methods: In 3290 adult subjects, plasma levels of triglycerides and HDL-cholesterol were cross-sectionally measured and related to interindividual variations in measures of insulin resistance in the liver (homeostasis mode assessment of insulin resistance index) or adipose tissue (Adipo-IR index).

Post-pancreatitis diabetes mellitus is common in chronic pancreatitis and is associated with adverse outcomes.

Background: Post-pancreatitis diabetes mellitus (PPDM) is a common consequence of chronic pancreatitis (CP). We aimed to determine the incidence and predictors of PPDM after CP onset, as well as complications and antidiabetic therapy requirements, in a high-volume tertiary center.

Methods: We did a cohort study with retrospectively collected data from patients with definite CP seen at the Karolinska University Hospital between January 1999 and December 2020.

Relationship Between a Sedentary Lifestyle and Adipose Insulin Resistance.

Sedentary people have insulin resistance in their skeletal muscle, but whether this also occurs in fat cells was unknown. Insulin inhibition of hydrolysis of triglycerides (antilipolysis) and stimulation of triglyceride formation (lipogenesis) were investigated in subcutaneous fat cells from 204 sedentary and 336 physically active subjects. Insulin responsiveness (maximum hormone effect) and sensitivity (half-maximal effective concentration) were determined.

Exocrine and Endocrine Insufficiency in Autoimmune Pancreatitis: A Matter of Treatment or Time?

Background: Autoimmune pancreatitis (AIP) is a specific form of chronic pancreatitis with a high relapse rate after treatment. AIP patients are burdened with an increased risk of long-term sequelae such as exocrine and endocrine insufficiency. Our objective was to investigate if pharmacological treatment affects both endocrine and exocrine pancreatic function in patients with AIP.

The long noncoding RNA ADIPINT regulates human adipocyte metabolism via pyruvate carboxylase.

The pleiotropic function of long noncoding RNAs is well recognized, but their direct role in governing metabolic homeostasis is less understood. Here, we describe a human adipocyte-specific lncRNA, ADIPINT, that regulates pyruvate carboxylase, a pivotal enzyme in energy metabolism. We developed an approach, Targeted RNA-protein identification using Orthogonal Organic Phase Separation, which identifies that ADIPINT binds to pyruvate carboxylase and validated the interaction with electron microscopy.

Long-term improvement of adipocyte insulin action during body weight relapse after bariatric surgery: a longitudinal cohort study.

Background: There are few long-term mechanistic studies in adipose tissue that investigate the metabolic effects of bariatric surgery. Changes in lipogenesis may be involved in long-term weight development.

Objectives: To investigate the long-term effect of bariatric surgery on lipogenesis in abdominal fat cells and whether surgical treatment could induce an epigenetic memory that would maintain improved lipogenesis in spite of body weight relapse.

Shared genetic loci for body fat storage and adipocyte lipolysis in humans.

Total body fat and central fat distribution are heritable traits and well-established predictors of adverse metabolic outcomes. Lipolysis is the process responsible for the hydrolysis of triacylglycerols stored in adipocytes. To increase our understanding of the genetic regulation of body fat distribution and total body fat, we set out to determine if genetic variants associated with body mass index (BMI) or waist-hip-ratio adjusted for BMI (WHRadjBMI) in genome-wide association studies (GWAS) mediate their effect by influencing adipocyte lipolysis.

Low Bone Mineral Density and Risk for Osteoporotic Fractures in Patients with Chronic Pancreatitis.

Chronic pancreatitis (CP) can lead to malnutrition, an established risk factor for low bone mineral density (BMD) and fractures. This study aims to determine the prevalence of low BMD, assess fracture incidence and explore risk factors for fractures in patients with CP. We performed a retrospective analysis of all patients treated for CP at Karolinska University Hospital between January 1999 and December 2020.

Adipose-specific inactivation of thyroid stimulating hormone receptors in mice modifies body weight, temperature and gene expression in adipocytes.

Background: In obesity, the expression level of thyroid stimulating hormone receptor in adipose tissue is reduced and the levels of thyroid stimulating hormone (TSH) are often elevated within the normal range.

Purpose/aim: To investigate the role of TSHR in brown and white adipose tissue (AT) using TSHR knockout (KO) mice and the physiological phenotypes affected by the TSHR knockout.

Methods: AT-specific TSHR KO male mice and wild type (WT) controls were given a high-fat diet (HFD) or a control diet (CD).

Age-Induced Reduction in Human Lipolysis: A Potential Role for Adipocyte Noradrenaline Degradation.

Gao et al. report that the observed reduction in adipose lipolysis with age in women could be explained by an upregulation of the catecholamine-degradation pathway in subcutaneous adipocytes. However, in contrast to findings in mice, these pathways are enriched in adipocytes and not in immune cells, suggesting species-specific differences in aging mechanisms.

Long-term changes in adipose tissue gene expression following bariatric surgery.

Objective: Patients undergoing bariatric surgery present long-term metabolic improvements and reduced type 2 diabetes risk, despite long-term weight regain. We hypothesized that part of these protective effects could be linked to altered gene expression in white adipose tissue (WAT).

Methods: Transcriptomic profiling by gene microarray was performed in abdominal subcutaneous WAT from women before (n = 50) and two (n = 49) and five (n = 38) years after Roux-en-Y gastric bypass (RYGB) surgery as well as in 28 age-matched nonoperated women.

Genome-Wide Association Study of Diabetogenic Adipose Morphology in the GENetics of Adipocyte Lipolysis (GENiAL) Cohort.

An increased adipocyte size relative to the size of fat depots, also denoted hypertrophic adipose morphology, is a strong risk factor for the future development of insulin resistance and type 2 diabetes. The regulation of adipose morphology is poorly understood We set out to identify genetic loci associated with adipose morphology and functionally evaluate candidate genes for impact on adipocyte development. We performed a genome-wide association study (GWAS) in the unique GENetics of Adipocyte Lipolysis (GENiAL) cohort comprising 948 participants who have undergone abdominal subcutaneous adipose biopsy with a determination of average adipose volume and morphology.

Genome-wide association study of adipocyte lipolysis in the GENetics of adipocyte lipolysis (GENiAL) cohort.

Objectives: Lipolysis, hydrolysis of triglycerides to fatty acids in adipocytes, is tightly regulated, poorly understood, and, if perturbed, can lead to metabolic diseases including obesity and type 2 diabetes. The goal of this study was to identify the genetic regulators of lipolysis and elucidate their molecular mechanisms.

Methods: Adipocytes from abdominal subcutaneous adipose tissue biopsies were isolated and were incubated without (spontaneous lipolysis) or with a catecholamine (stimulated lipolysis) to analyze lipolysis.

An Isocaloric Nordic Diet Modulates and Gene Expression in Peripheral Blood Mononuclear Cells in Individuals with Metabolic Syndrome-A SYSDIET Sub-Study.

A healthy dietary pattern is associated with a lower risk of metabolic syndrome (MetS) and reduced inflammation. To explore this at the molecular level, we investigated the effect of a Nordic diet (ND) on changes in the gene expression profiles of inflammatory and lipid-related genes in peripheral blood mononuclear cells (PBMCs) of individuals with MetS. We hypothesized that the intake of an ND compared to a control diet (CD) would alter the expression of inflammatory genes and genes involved in lipid metabolism.

Evaluation of the Genetic Association Between Adult Obesity and Neuropsychiatric Disease.

Extreme obesity (EO) (BMI >50 kg/m) is frequently associated with neuropsychiatric disease (NPD). As both EO and NPD are heritable central nervous system disorders, we assessed the prevalence of protein-truncating variants (PTVs) and copy number variants (CNVs) in genes/regions previously implicated in NPD in adults with EO ( = 149) referred for weight loss/bariatric surgery. We also assessed the prevalence of CNVs in patients referred to University College London Hospital (UCLH) with EO ( = 218) and obesity (O) (BMI 35-50 kg/m; = 374) and a Swedish cohort of participants from the community with predominantly O ( = 161).

Prospective analyses of white adipose tissue gene expression in relation to long-term body weight changes.

Background: Transcriptome analysis of abdominal subcutaneous white adipose tissue (sWAT) has identified important obesity-associated disturbances. However, the relation between sWAT transcriptome and long-term future changes in body weight remains elusive.

Objective: To investigate sWAT transcriptome signatures before and after long-term weight changes and assess their predictive value for body weight changes.

MicroRNA-196a links human body fat distribution to adipose tissue extracellular matrix composition.

Background: Abdominal fat mass is associated with metabolic risk whilst gluteal femoral fat is paradoxically protective. MicroRNAs are known to be necessary for adipose tissue formation and function but their role in regulating human fat distribution remains largely unexplored.

Methods: An initial microarray screen of abdominal subcutaneous and gluteal adipose tissue, with validatory qPCR, identified microRNA-196a as being strongly differentially expressed between gluteal and abdominal subcutaneous adipose tissue.

Epigenetic regulation of diabetogenic adipose morphology.

Objective: Hypertrophic white adipose tissue (WAT) morphology is associated with insulin resistance and type 2 diabetes. The mechanisms governing hyperplastic versus hypertrophic WAT expansion are poorly understood. We assessed if epigenetic modifications in adipocytes are associated with hypertrophic adipose morphology.