LRP5 promotes adipose progenitor cell fitness and adipocyte insulin sensitivity.

Background: WNT signaling plays a key role in postnatal bone formation. Individuals with gain-of-function mutations in the WNT co-receptor LRP5 exhibit increased lower-body fat mass and potentially enhanced glucose metabolism, alongside high bone mass. However, the mechanisms by which LRP5 regulates fat distribution and its effects on systemic metabolism remain unclear.

Inconsistency in ferritin reference intervals across laboratories: a major concern for clinical decision making.

Objectives: Iron deficiency anemia is a significant global health concern, diagnosed by measuring hemoglobin concentrations in combination with plasma ferritin concentration. This study investigated the variability in ferritin reference intervals among laboratories in the Netherlands and examined how this affects the identification of iron-related disorders.

Methods: Ferritin reference intervals from 52 Dutch ISO15189-certified medical laboratories were collected.

Immunoproteasomal Inhibition With ONX-0914 Attenuates Atherosclerosis and Reduces White Adipose Tissue Mass and Metabolic Syndrome in Mice.

Background: Atherosclerosis is the major underlying pathology of cardiovascular disease and is driven by dyslipidemia and inflammation. Inhibition of the immunoproteasome, a proteasome variant that is predominantly expressed by immune cells and plays an important role in antigen presentation, has been shown to have immunosuppressive effects.

Methods: We assessed the effect of ONX-0914, an inhibitor of the immunoproteasomal catalytic subunits LMP7 (proteasome subunit β5i/large multifunctional peptidase 7) and LMP2 (proteasome subunit β1i/large multifunctional peptidase 2), on atherosclerosis and metabolism in LDLr and APOE*3-Leiden.

HOTAIR interacts with PRC2 complex regulating the regional preadipocyte transcriptome and human fat distribution.

Mechanisms governing regional human adipose tissue (AT) development remain undefined. Here, we show that the long non-coding RNA HOTAIR (HOX transcript antisense RNA) is exclusively expressed in gluteofemoral AT, where it is essential for adipocyte development. We find that HOTAIR interacts with polycomb repressive complex 2 (PRC2) and we identify core HOTAIR-PRC2 target genes involved in adipocyte lineage determination.

TCF7L2 plays a complex role in human adipose progenitor biology, which might contribute to genetic susceptibility to type 2 diabetes.

Introduction: Non-coding genetic variation at TCF7L2 is the strongest genetic determinant of type 2 diabetes (T2D) risk in humans. TCF7L2 encodes a transcription factor mediating the nuclear effects of WNT signaling in adipose tissue (AT). In vivo studies in transgenic mice have highlighted important roles for TCF7L2 in adipose tissue biology and systemic metabolism.

Higher Plasma Sclerostin and Lower Wnt Signaling Gene Expression in White Adipose Tissue of Prediabetic South Asian Men Compared with White Caucasian Men.

Background: South Asians generally have an unfavourable metabolic phenotype compared with white Caucasians, including central obesity and insulin resistance. The Wnt protein family interacts with insulin signaling, and impaired Wnt signaling is associated with adiposity and type 2 diabetes mellitus. We aimed to investigate Wnt signaling in relation to insulin signaling in South Asians compared with white Caucasians.

Conditionally immortalized brown preadipocytes can switch between proliferative and differentiated states.

Brown adipose tissue (BAT) is a potential target to treat cardiometabolic disorders because of its capacity to combust glucose and fatty acids for thermoregulation. Its cellular and molecular investigation in humans is hampered by the limited availability of cell material and the heterogeneity of BAT between and within individuals. In this study, monoclonal lines of conditionally immortalized brown preadipocytes (iBPAs) of mouse and human origin were generated.

IL-37 Expression Reduces Lean Body Mass in Mice by Reducing Food Intake.

The human cytokine interleukin (IL)-37 is an anti-inflammatory member of the IL-1 family of cytokines. Transgenic expression of IL-37 in mice protects them from diet-induced obesity and associated metabolic complications including dyslipidemia, inflammation and insulin resistance. The precise mechanism of action leading to these beneficial metabolic effects is not entirely known.

Quercetin Lowers Plasma Triglycerides Accompanied by White Adipose Tissue Browning in Diet-Induced Obese Mice.

Obesity and dyslipidemia are major risk factors for the development of cardiovascular diseases (CVD). Quercetin, a natural flavonoid, lowers plasma triglycerides (TG) in human intervention studies, and its intake is associated with lower CVD risk. The aim of this study was to elucidate the mechanism by which quercetin lowers plasma TG levels in diet-induced obesity.

The GPR120 agonist TUG-891 promotes metabolic health by stimulating mitochondrial respiration in brown fat.

Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein-coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120-mediated signaling in BAT We found that activation of GPR120 by the selective agonist TUG-891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice.

Atorvastatin accelerates clearance of lipoprotein remnants generated by activated brown fat to further reduce hypercholesterolemia and atherosclerosis.

Background And Aims: Activation of brown adipose tissue (BAT) reduces both hyperlipidemia and atherosclerosis by increasing the uptake of triglyceride-derived fatty acids by BAT, accompanied by formation and clearance of lipoprotein remnants. We tested the hypothesis that the hepatic uptake of lipoprotein remnants generated by BAT activation would be accelerated by concomitant statin treatment, thereby further reducing hypercholesterolemia and atherosclerosis.

Methods: APOE*3-Leiden.

Helminth antigens counteract a rapid high-fat diet-induced decrease in adipose tissue eosinophils.

Brown adipose tissue (BAT) activation and white adipose tissue (WAT) beiging can increase energy expenditure and have the potential to reduce obesity and associated diseases. The immune system is a potential target in mediating brown and beige adipocyte activation. Type 2 and anti-inflammatory immune cells contribute to metabolic homeostasis within lean WAT, with a prominent role for eosinophils and interleukin (IL)-4-induced anti-inflammatory macrophages.

Targeting white, brown and perivascular adipose tissue in atherosclerosis development.

Obesity is a well-established risk factor for atherosclerosis. However, the mechanistic link between accumulation of adipose tissue and development of atherosclerosis is not clear. Adipose tissue comprises various depots including white adipose tissue (WAT), brown adipose tissue (BAT) and thoracic and abdominal perivascular adipose tissue (PVAT).

Immune Modulation of Brown(ing) Adipose Tissue in Obesity.

Obesity is associated with a variety of medical conditions such as type 2 diabetes and cardiovascular diseases and is therefore responsible for high morbidity and mortality rates. Increasing energy expenditure by brown adipose tissue (BAT) is a current novel strategy to reduce the excessive energy stores in obesity. Brown adipocytes burn energy to generate heat and are mainly activated upon cold exposure.

BCG lowers plasma cholesterol levels and delays atherosclerotic lesion progression in mice.

Background And Aims: Bacille-Calmette-Guérin (BCG), prepared from attenuated live Mycobacterium bovis, modulates atherosclerosis development as currently explained by immunomodulatory mechanisms. However, whether BCG is pro- or anti-atherogenic remains inconclusive as the effect of BCG on cholesterol metabolism, the main driver of atherosclerosis development, has remained underexposed in previous studies. Therefore, we aimed to elucidate the effect of BCG on cholesterol metabolism in addition to inflammation and atherosclerosis development in APOE*3-Leiden.

FcRγ-chain deficiency reduces the development of diet-induced obesity.

Objective: Pathogenic immunoglobulins are produced during the development of obesity and contribute to the development of insulin resistance (IR). However, the mechanisms by which these antibodies affect IR are largely unknown. This study investigated whether Fc-receptors contribute to the development of diet-induced obesity and IR by studying FcRγ(-/-) mice that lack the γ-subunit necessary for signaling and cell surface expression of FcγR and FcεRI.

Salsalate attenuates diet induced non-alcoholic steatohepatitis in mice by decreasing lipogenic and inflammatory processes.

Background And Purpose: Salsalate (salicylsalicylic acid) is an anti-inflammatory drug that was recently found to exert beneficial metabolic effects on glucose and lipid metabolism. Although its utility in the prevention and management of a wide range of vascular disorders, including type 2 diabetes and metabolic syndrome has been suggested before, the potential of salsalate to protect against non-alcoholic steatohepatitis (NASH) remains unclear. The aim of the present study was therefore to ascertain the effects of salsalate on the development of NASH.

Regulation of brown fat by AMP-activated protein kinase.

Novel strategies are needed to reduce the obesity epidemic. One promising strategy is activation of brown adipose tissue (BAT), either via the brain or directly, which increases energy expenditure by combustion of fatty acids (FAs) into heat. The enzyme complex AMP-activated protein kinase (AMPK) is crucially involved in energy metabolism and is highly expressed in both brain and BAT, regulating thermogenesis.

Plasma cholesteryl ester transfer protein is predominantly derived from Kupffer cells.

Unlabelled: The role of Kupffer cells (KCs) in the pathophysiology of the liver has been firmly established. Nevertheless, KCs have been underexplored as a target for diagnosis and treatment of liver diseases owing to the lack of noninvasive diagnostic tests. We addressed the hypothesis that cholesteryl ester transfer protein (CETP) is mainly derived from KCs and may predict KC content.

The limited storage capacity of gonadal adipose tissue directs the development of metabolic disorders in male C57Bl/6J mice.

Aims/hypothesis: White adipose tissue (WAT) consists of various depots with different adipocyte functionality and immune cell composition. Knowledge of WAT-depot-specific differences in expandability and immune cell influx during the development of obesity is limited, therefore we aimed to characterise different WAT depots during the development of obesity in mice.

Methods: Gonadal WAT (gWAT), subcutaneous WAT (sWAT) and mesenteric WAT (mWAT) were isolated from male C57Bl/6J mice with different body weights (approximately 25-60 g) and analysed.

Salsalate activates brown adipose tissue in mice.

Salsalate improves glucose intolerance and dyslipidemia in type 2 diabetes patients, but the mechanism is still unknown. The aim of the current study was to unravel the molecular mechanisms involved in these beneficial metabolic effects of salsalate by treating mice with salsalate during and after development of high-fat diet-induced obesity. We found that salsalate attenuated and reversed high-fat diet-induced weight gain, in particular fat mass accumulation, improved glucose tolerance, and lowered plasma triglyceride levels.

Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity.

The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis, and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintenance of weight loss and reduction of dyslipidemia in experimental and human obesity. The molecular mechanism by which CB1R blockade reverses dyslipidemia in obesity has not yet been clarified.