A multi-scale digital twin for adiposity-driven insulin resistance in humans: diet and drug effects.

Background: The increased prevalence of insulin resistance is one of the major health risks in society today. Insulin resistance involves both short-term dynamics, such as altered meal responses, and long-term dynamics, such as the development of type 2 diabetes. Insulin resistance also occurs on different physiological levels, ranging from disease phenotypes to organ-organ communication and intracellular signaling.

Adipocyte traits limiting cellular insulin responsiveness and glucose transport.

Adipocyte dysfunction is a hallmark of systemic insulin resistance. Insulin-responsive glucose transporter 4 (GLUT4) is downregulated in the insulin resistant state, and cellular insulin responsiveness varies depending on fat depot origin and degree of adipose expansion. Here, we have resolved factors limiting cellular insulin responsiveness, by examining adipocyte function and traits related to glucose transport at the cellular level.

Altered Adipocyte Cell Size Distribution Prior to Weight Loss in the R6/2 Model of Huntington's Disease.

Background: Metabolic alterations contribute to disease onset and prognosis of Huntington's disease (HD). Weight loss in the R6/2 mouse model of HD is a consistent feature, with onset in mid-to-late stage of disease.

Objective: In the present study, we aimed to investigate molecular and functional changes in white adipose tissue (WAT) that occur at weight loss in R6/2 mice.

EHD2 regulates plasma membrane integrity and downstream insulin receptor signaling events.

Adipocyte dysfunction is a crucial driver of insulin resistance and type 2 diabetes. We identified EH domain-containing protein 2 (EHD2) as one of the most highly upregulated genes at the early stage of adipose-tissue expansion. EHD2 is a dynamin-related ATPase influencing several cellular processes, including membrane recycling, caveolae dynamics, and lipid metabolism.

Salt-inducible kinases are required for glucose uptake and insulin signaling in human adipocytes.

Objective: Salt-inducible kinase 2 (SIK2) is abundantly expressed in adipocytes and downregulated in adipose tissue from individuals with obesity or insulin resistance. The main aims of this work were to investigate the involvement of SIKs in the regulation of glucose uptake in primary mature human adipocytes and to identify mechanisms underlying this regulation.

Methods: Primary mature adipocytes were isolated from human, rat, or mouse adipose tissue and treated with pan-SIK inhibitors.

Acute cytokine treatment stimulates glucose uptake and glycolysis in human keratinocytes.

During inflammation, cellular glucose uptake and glycolysis are upregulated to meet an increased energy demand. For example, keratinocyte glycolysis is essential for progression of psoriasis. Therefore, understanding the regulation of glucose metabolism in keratinocytes is of importance.

Expansion of the Inguinal Adipose Tissue Depot Correlates With Systemic Insulin Resistance in C57BL/6J Mice.

To accommodate surplus energy, the adipose tissue expands by increasing adipocyte size (hypertrophy) and number (hyperplasia). The presence of hypertrophic adipocytes is a key characteristic of adipose tissue dysfunction. High-fat diet (HFD) fed C57BL/6J mice are a commonly used model to study obesity and obesity-related complications.

Postprandial triglyceride levels rather than fat distribution may reflect early signs of disturbed fat metabolism in Iraqi immigrants.

Purpose: Previous studies have shown that at a similar body mass index, Middle Eastern immigrants are more insulin resistant and at higher risk for type 2 diabetes (T2D) than native Europeans. Insulin resistance is strongly associated with disturbed fat metabolism and cardiovascular disease (CVD). However, fat metabolism is poorly investigated comparing Middle Eastern and European ethnicities.

Myocardin regulates exon usage in smooth muscle cells through induction of splicing regulatory factors.

Differentiation of smooth muscle cells (SMCs) depends on serum response factor (SRF) and its co-activator myocardin (MYOCD). The role of MYOCD for the SMC program of gene transcription is well established. In contrast, the role of MYOCD in control of SMC-specific alternative exon usage, including exon splicing, has not been explored.

Rosiglitazone treatment enhances intracellular actin dynamics and glucose transport in hypertrophic adipocytes.

Aims: To accommodate surplus energy, adipose tissue expands by increasing both adipose cell size (hypertrophy) and cell number (hyperplasia). Enlarged, hypertrophic adipocytes are known to have reduced insulin response and impaired glucose transport, which negatively influence whole-body glucose homeostasis. Rosiglitazone is a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, known to stimulate hyperplasia and to efficiently improve insulin sensitivity.

Favorable fatty acid composition in adipose tissue in healthy Iraqi- compared to Swedish-born men - a pilot study using MRI assessment.

Middle Eastern immigrants are at high-risk for insulin resistance. Fatty acid composition (FAC) plays an important role in the development of insulin resistance but has not been investigated in people of Middle Eastern ancestry. Here, the aim was to assess the FAC in visceral and subcutaneous adipose tissue (VAT and SAT) in healthy Iraqi- and Swedish-born men using a magnetic resonance imaging (MRI) method.

Insulin regulates Nedd4-2 via a PKB-dependent mechanism in HEI-OC1 auditory cells-crosstalks with sphingolipid and cAMP signaling.

Background: The mechanisms of association between diabetes and inner ear dysfunction are unknown, although endolymphatic hydrops may be involved. We have previously shown that insulin signaling components are expressed in human saccule and that insulin signaling takes place in HEI-OC1 auditory cells.

Aim: To explore Nedd4-2 as a target for insulin signaling.

Cell Type Dependent Suppression of Inflammatory Mediators by Myocardin Related Transcription Factors.

Myocardin related transcription factors (MRTFs: MYOCD/myocardin, MRTF-A, and MRTF-B) play a key role in smooth muscle cell differentiation by activating contractile genes. In atherosclerosis, MRTF levels change, and most notable is a fall of MYOCD. Previous work described anti-inflammatory properties of MRTF-A and MYOCD, occurring through RelA binding, suggesting that MYOCD reduction could contribute to vascular inflammation.

EH Domain-Containing 2 Deficiency Restricts Adipose Tissue Expansion and Impairs Lipolysis in Primary Inguinal Adipocytes.

Lipid uptake can be facilitated caveolae, specific plasma membrane invaginations abundantly expressed in adipocytes. The dynamin-related protein EH domain-containing 2 (EHD2) stabilizes caveolae at the cell surface. Here, we have examined the importance of EHD2 for lipid handling using primary adipocytes isolated from EHD2 knockout ( ) C57BL6/N mice.

The Importance of Food for Endotoxemia and an Inflammatory Response.

Bacterial endotoxin is a potent inflammatory antigen abundant in the human intestine. Endotoxins circulate in the blood at low concentrations in all healthy individuals. Elevated levels of circulatory endotoxins may cause inflammation with the development of chronic disease, either affecting metabolism, neurological disease, or resistance to viral and bacterial infections.

NG2/CSPG4, CD146/MCAM and VAP1/AOC3 are regulated by myocardin-related transcription factors in smooth muscle cells.

The present work addressed the hypothesis that NG2/CSPG4, CD146/MCAM, and VAP1/AOC3 are target genes of myocardin-related transcription factors (MRTFs: myocardin/MYOCD, MRTF-A/MKL1, MRTF-B/MKL2) and serum response factor (SRF). Using a bioinformatics approach, we found that CSPG4, MCAM, and AOC3 correlate with MYOCD, MRTF-A/MKL1, and SRF across human tissues. No other transcription factor correlated as strongly with these transcripts as SRF.

Surface-associated lipid droplets: an intermediate site for lipid transport in human adipocytes?

Adipose tissue plays a major role in regulating whole-body energy metabolism. While the biochemical processes regulating storage and release of excess energy are well known, the temporal organization of these events is much less defined. In this study, we have characterized the presence of small surface-associated lipid droplets, distinct from the central droplet, in primary human adipocytes.

A short peptide of the C-terminal class Y helices of apolipoprotein A-I has preserved functions in cholesterol efflux and in vivo metabolic control.

Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) induces glucose uptake by muscle tissues and stimulates pancreatic insulin secretion, and also facilitates cholesterol transport in circulation, and is explored for anti-diabetic and anti-atherosclerotic treatments. As the better alternative to complex protein-lipid formulations it was recently established that the C-terminal region of the ApoA-I protein singly improves the metabolic control and prevents formation of atherosclerotic plaques. Additional investigations of peptides based on the ApoA-I structure may lead to novel anti-diabetic drugs.

A hypothesis for insulin resistance in primary human adipocytes involving MRTF-A and suppression of PPARγ.

Obesity is the main risk factor behind insulin resistance and type 2 diabetes. Still, the mechanism behind adipocyte dysfunction is not yet resolved. Recently, we reported that rapid actin remodeling correlates with adipose cell size changes after short-term overfeeding.

Inner ear is a target for insulin signaling and insulin resistance: evidence from mice and auditory HEI-OC1 cells.

Objective: The mechanisms underlying the association between diabetes and inner ear dysfunction are not known yet. The aim of the present study is to evaluate the impact of obesity/insulin resistance on inner ear fluid homeostasis in vivo, and to investigate whether the organ of Corti could be a target tissue for insulin signaling using auditory House Ear Institute-Organ of Corti 1 (HEI-OC1) cells as an in vitro model.

Methods: High fat diet (HFD) fed C57BL/6J mice were used as a model to study the impact of insulin resistance on the inner ear.

Impaired glucose transport in inguinal adipocytes after short-term high-sucrose feeding in mice.

Diets enriched in sucrose severely impair metabolic regulation and are associated with obesity, insulin resistance and glucose intolerance. In the current study, we investigated the effect of 4 weeks high-sucrose diet (HSD) feeding in C57BL6/J mice, with specific focus on adipocyte function. Mice fed HSD had slightly increased adipose tissue mass but displayed similar hepatic triglycerides, glucose and insulin levels, and glucose clearance capacity as chow-fed mice.

Adipose cell size changes are associated with a drastic actin remodeling.

Adipose tissue plays a major role in regulating whole-body insulin sensitivity and energy metabolism. To accommodate surplus energy, the tissue rapidly expands by increasing adipose cell size (hypertrophy) and cell number (hyperplasia). Previous studies have shown that enlarged, hypertrophic adipocytes are less responsive to insulin, and that adipocyte size could serve as a predictor for the development of type 2 diabetes.

Identification of the intermediate filament protein synemin/SYNM as a target of myocardin family coactivators.

Myocardin (MYOCD) is a critical regulator of smooth muscle cell (SMC) differentiation, but its transcriptional targets remain to be exhaustively characterized, especially at the protein level. Here we leveraged human RNA and protein expression data to identify novel potential MYOCD targets. Using correlation analyses we found several targets that we could confirm at the protein level, including SORBS1, SLMAP, SYNM, and MCAM.

ApoAI-derived peptide increases glucose tolerance and prevents formation of atherosclerosis in mice.

Aims/hypothesis: Finding new treatment alternatives for individuals with diabetes with severe insulin resistance is highly desired. To identify novel mechanisms that improve glucose uptake in skeletal muscle, independently from insulin levels and signalling, we have explored the therapeutic potential of a short peptide sequence, RG54, derived from apolipoprotein A-I (ApoA-I).

Methods: INS-1E rat clonal beta cells, C2C12 rat muscle myotubes and J774 mouse macrophages were used to study the impact of RG54 peptide on glucose-stimulated insulin secretion, glucose uptake and cholesterol efflux, respectively.