Interaction of Vitamin D-BODIPY With Fat Cells and the Link to Obesity-associated Vitamin D Deficiency.

Background/aim: Obese individuals often exhibit vitamin D deficiency, potentially due to sequestration in fat cells. Little is known about how vitamin D enters adipocytes and associates with the intracellular lipid droplet.

Materials And Methods: Newly differentiated human and mouse (3T3-L1) adipocytes and primary mouse adipocytes were treated with vitamin D covalently linked to green fluorescent BODIPY (VitD-B) or Green BODIPY (GB) as control.

Resolvin E1 heals injured cardiomyocytes: Therapeutic implications and H-FABP as a readout for cardiovascular disease & systemic inflammation.

The purpose of this study is to investigate heart-fatty acid binding protein (H-FABP) leakage from cardiomyocytes as a quantitative measure of cell membrane damage and to test healing by Resolvin E1 (RVE1) as a potential therapeutic for patients with inflammatory diseases (cardiovascular disease and comorbidities) with high morbidity and mortality. Our quantitative ELISA assays demonstrated H-FABP as a sensitive and reliable biomarker for measuring cardiomyocyte damage induced by lipopolysaccharide (LPS) and healing by RvE1, a specialized pro-resolving mediator (SPM) derived from the Omega-3 fatty acid, eicosapentaenoic acid (EPA), a dietary nutrient that balances inflammation to restore homeostasis. RvE1 reduced leakage of H-FABP by up to 86%, which supports our hypothesis that inflammation as a mechanism of injury can be targeted for therapy.

Dairy Foods, Weight Change, and Risk of Obesity During the Menopausal Transition.

Background: Weight gain during the menopausal transition is common. Dairy consumption may impact weight change during this critical period, and different dairy foods may have different effects.

Objectives: This study aimed to investigate the associations of different types of dairy foods with weight gain and risk of obesity in perimenopausal women from the Nurses' Health Study II cohort.

Dairy Food Intakes, Postpartum Weight Retention, and Risk of Obesity.

Excessive postpartum weight retention puts women at risk for health problems. This study aimed to investigate the effects of dairy foods on weight retention and risk of obesity in postpartum women in the Nurses’ Health Study II. Weight was reported every 2 years.

What Regulates Basal Insulin Secretion and Causes Hyperinsulinemia?

We hypothesize that basal hyperinsulinemia is synergistically mediated by an interplay between increased oxidative stress and excess lipid in the form of reactive oxygen species (ROS) and long-chain acyl-CoA esters (LC-CoA). In addition, ROS production may increase in response to inflammatory cytokines and certain exogenous environmental toxins that mislead β-cells into perceiving nutrient excess when none exists. Thus, basal hyperinsulinemia is envisioned as an adaptation to sustained real or perceived nutrient excess that only manifests as a disease when the excess demand can no longer be met by an overworked β-cell.

The Redox Communication Network as a Regulator of Metabolism.

Key tissues are dysfunctional in obesity, diabetes, cardiovascular disease, fatty liver and other metabolic diseases. Focus has centered on individual organs as though each was isolated. Attention has been paid to insulin resistance as the key relevant pathosis, particularly insulin receptor signaling.

Metformin Enhances Autophagy and Normalizes Mitochondrial Function to Alleviate Aging-Associated Inflammation.

Age is a non-modifiable risk factor for the inflammation that underlies age-associated diseases; thus, anti-inflammaging drugs hold promise for increasing health span. Cytokine profiling and bioinformatic analyses showed that Th17 cytokine production differentiates CD4 T cells from lean, normoglycemic older and younger subjects, and mimics a diabetes-associated Th17 profile. T cells from older compared to younger subjects also had defects in autophagy and mitochondrial bioenergetics that associate with redox imbalance.

Exposure of Pancreatic β-Cells to Excess Glucose Results in Bimodal Activation of mTORC1 and mTOR-Dependent Metabolic Acceleration.

Chronic exposure of pancreatic β-cells to excess glucose can lead to metabolic acceleration and loss of stimulus-secretion coupling. Here, we examined how exposure to excess glucose (defined here as concentrations above 5 mM) affects mTORC1 signaling and the metabolism of β-cells. Acute exposure to excess glucose stimulated glycolysis-dependent mTORC1 signaling, without changes in the PI3K or AMPK pathways.

Effects of medium chain triglycerides supplementation on insulin sensitivity and beta cell function: A feasibility study.

Objective: Medium chain triglycerides (MCT) have unique metabolic properties which may improve insulin sensitivity (Si) and beta cell function but data in humans are limited. We conducted a 6-week clinical trial of MCT oil supplementation.

Methods: 22 subjects without diabetes (8 males, 14 females, mean ± standard error age 39±2.

Elamipretide Promotes Mitophagosome Formation and Prevents Its Reduction Induced by Nutrient Excess in INS1 β-cells.

Elamipretide is a tetrapeptide that restores defects in mitochondrial function, binds to cardiolipin, and is being tested in clinical trials for mitochondria-related diseases. However, whether elamipretide modulates mitochondrial quality control and dynamics, processes essential to preserve mitochondrial function, is unclear. Thus, we tested the effects of elamipretide on mitochondrial morphology, mitophagosome formation, and their early disruption induced by excess nutrients in INS1 β-cells.

BET proteins in abnormal metabolism, inflammation, and the breast cancer microenvironment.

Obesity and its associated pathology Type 2 diabetes are two chronic metabolic and inflammatory diseases that promote breast cancer progression, metastasis, and poor outcomes. Emerging critical opinion considers unresolved inflammation and abnormal metabolism separately from obesity; settings where they do not co-occur can inform disease mechanism. In breast cancer, the tumor microenvironment is often infiltrated with T effector and T regulatory cells programmed by metabolic signaling.

Type 1 diabetes alters lipid handling and metabolism in human fibroblasts and peripheral blood mononuclear cells.

Triggers of the autoimmune response that leads to type 1 diabetes (T1D) remain poorly understood. A possibility is that parallel changes in both T cells and target cells provoke autoimmune attack. We previously documented greater Ca2+ transients in fibroblasts from T1D subjects than non-T1D after exposure to fatty acids (FA) and tumor necrosis factor α (TNFα).

Direct Stimulation of Islet Insulin Secretion by Glycolytic and Mitochondrial Metabolites in KCl-Depolarized Islets.

We have previously demonstrated that islet depolarization with 70 mM KCl opens Cx36 hemichannels and allows diffusion of small metabolites and cofactors through the β-cell plasma membrane. We have investigated in this islet "permeabilized" model whether glycolytic and citric acid cycle intermediates stimulate insulin secretion and how it correlates with ATP production (islet content plus extracellular nucleotide accumulation). Glycolytic intermediates (10 mM) stimulated insulin secretion and ATP production similarly.

BET Bromodomain Proteins Brd2, Brd3 and Brd4 Selectively Regulate Metabolic Pathways in the Pancreatic β-Cell.

Displacement of Bromodomain and Extra-Terminal (BET) proteins from chromatin has promise for cancer and inflammatory disease treatments, but roles of BET proteins in metabolic disease remain unexplored. Small molecule BET inhibitors, such as JQ1, block BET protein binding to acetylated lysines, but lack selectivity within the BET family (Brd2, Brd3, Brd4, Brdt), making it difficult to disentangle contributions of each family member to transcriptional and cellular outcomes. Here, we demonstrate multiple improvements in pancreatic β-cells upon BET inhibition with JQ1 or BET-specific siRNAs.

Phosphoinositide signalling in type 2 diabetes: a β-cell perspective.

Type 2 diabetes is a complex disease. It results from a failure of the body to maintain energy homoeostasis. Multicellular organisms have evolved complex strategies to preserve a relatively stable internal nutrient environment, despite fluctuations in external nutrient availability.

Inborn Errors of Long-Chain Fatty Acid β-Oxidation Link Neural Stem Cell Self-Renewal to Autism.

Inborn errors of metabolism (IEMs) occur with high incidence in human populations. Especially prevalent among these are inborn deficiencies in fatty acid β-oxidation (FAO), which are clinically associated with developmental neuropsychiatric disorders, including autism. We now report that neural stem cell (NSC)-autonomous insufficiencies in the activity of TMLHE (an autism risk factor that supports long-chain FAO by catalyzing carnitine biosynthesis), of CPT1A (an enzyme required for long-chain FAO transport into mitochondria), or of fatty acid mobilization from lipid droplets reduced NSC pools in the mouse embryonic neocortex.

KCl -Permeabilized Pancreatic Islets: An Experimental Model to Explore the Messenger Role of ATP in the Mechanism of Insulin Secretion.

Our previous work has demonstrated that islet depolarization with KCl opens connexin36 hemichannels in β-cells of mouse pancreatic islets allowing the exchange of small metabolites with the extracellular medium. In this study, the opening of these hemichannels has been further characterized in rat islets and INS-1 cells. Taking advantage of hemicannels'opening, the uptake of extracellular ATP and its effect on insulin release were investigated.

Chronic Exposure to Excess Nutrients Left-shifts the Concentration Dependence of Glucose-stimulated Insulin Secretion in Pancreatic β-Cells.

Hyperinsulinemia (HI) is elevated plasma insulin at basal glucose. Impaired glucose tolerance is associated with HI, although the exact cause and effect relationship remains poorly defined. We tested the hypothesis that HI can result from an intrinsic response of the β-cell to chronic exposure to excess nutrients, involving a shift in the concentration dependence of glucose-stimulated insulin secretion.

Brd2 gene disruption causes "metabolically healthy" obesity: epigenetic and chromatin-based mechanisms that uncouple obesity from type 2 diabetes.

Disturbed body energy balance can lead to obesity and obesity-driven diseases such as Type 2 diabetes, which have reached an epidemic level. Evidence indicates that obesity-induced inflammation is a major cause of insulin resistance and Type 2 diabetes. Environmental factors, such as nutrients, affect body energy balance through epigenetic or chromatin-based mechanisms.

Reactive oxygen species stimulate insulin secretion in rat pancreatic islets: studies using mono-oleoyl-glycerol.

Chronic exposure (24-72 hrs) of pancreatic islets to elevated glucose and fatty acid leads to glucolipoxicity characterized by basal insulin hypersecretion and impaired glucose-stimulated insulin secretion (GSIS). Our aim was to determine the mechanism for basal hypersecretion of insulin. We used mono-oleoyl-glycerol (MOG) as a tool to rapidly increase lipids in isolated rat pancreatic ß-cells and in the clonal pancreatic ß-cell line INS-1 832/13.

Respiration in adipocytes is inhibited by reactive oxygen species.

It is a desirable goal to stimulate fuel oxidation in adipocytes and shift the balance toward less fuel storage and more burning. To understand this regulatory process, respiration was measured in primary rat adipocytes, mitochondria, and fat-fed mice. Maximum O(2) consumption, in vitro, was determined with a chemical uncoupler of oxidative phosphorylation (carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)).

The CB1 antagonist rimonabant decreases insulin hypersecretion in rat pancreatic islets.

Type 2 diabetes and obesity are characterized by elevated nocturnal circulating free fatty acids, elevated basal insulin secretion, and blunted glucose-stimulated insulin secretion (GSIS). The CB1 receptor antagonist, Rimonabant, has been shown to improve glucose tolerance and insulin sensitivity in vivo but its direct effect on islets has been unclear. Islets from lean littermates and obese Zucker (ZF) and Zucker Diabetic Fatty (ZDF) rats were incubated for 24 h in vitro and exposed to 11 mmol/l glucose and 0.

Dual role of proapoptotic BAD in insulin secretion and beta cell survival.

The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain.