Andrea D. van Dam

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. In this study, we showed that CB1R blockade with the systemic CB1R blocker rimonabant enhanced whole‐body energy expenditure and activated brown adipose tissue (BAT), indicated by increased expression of genes involved in BAT thermogenesis and decreased lipid droplet size in BAT. This was accompanied by selectively increased triglyceride (TG) uptake by BAT and lower plasma TG levels. Interestingly, the effects on BAT activation were still present at thermoneutrality and could be recapitulated by using the strictly peripheral CB1R antagonist AM6545, indicating direct peripheral activation of BAT. Indeed, CB1R blockade directly activated T37i brown adipocytes, resulting in enhanced uncoupled respiration, most likely via enhancing cAMP/PKA signaling via the adrenergic receptor pathway. Our data indicate that selective targeting of the peripheral CB1R in BAT has therapeutic potential in attenuating dyslipidemia and obesity.—Boon, M. R., Kooijman, S., van Dam, A. D., Pelgrom, L. R., Berbée, J. F. P., Visseren, C. A. R., van Aggele, R. C., van den Hoek, A. M., Sips, H. C. M., Lombès, M., Havekes, L. M., Tamsma, J. T., Guigas, B., Meijer, O. C., Jukema, J. W., Rensen, P. C. N., Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity. FASEB J. 28, 5361–5375 (2014). www.fasebj.org

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. As a general rule, BAT activity and energy expenditure are increased either by suppression of AMPK activity in the brain, resulting in enhanced sympathetic outflow towards BAT, or by activation of AMPK in BAT. Targeting AMPK may thus hold therapeutic potential for the treatment of obesity and related disorders.

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. Mechanistically, salsalate selectively promoted the uptake of fatty acids from glycerol tri[3H]oleate-labeled lipoprotein-like emulsion particles by brown adipose tissue (BAT), decreased the intracellular lipid content in BAT, and increased rectal temperature, all pointing to more active BAT. The treatment of differentiated T37i brown adipocytes with salsalate increased uncoupled respiration. Moreover, salsalate upregulated Ucp1 expression and enhanced glycerol release, a dual effect that was abolished by the inhibition of cAMP-dependent protein kinase (PKA). In conclusion, salsalate activates BAT, presumably by directly activating brown adipocytes via the PKA pathway, suggesting a novel mechanism that may explain its beneficial metabolic effects in type 2 diabetes patients.

Targeting white, brown and perivascular adipose tissue in atherosclerosis development

Abstract 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). The phenotype of thoracic PVAT resembles BAT, whereas abdominal PVAT is more like WAT. Here, we review the distinct roles of the adipose tissue depots in the development of atherosclerosis with the ultimate aim to understand how these can be targeted to reduce atherosclerosis. In obesity, increased fatty acid release by WAT and decreased lipid combustion by BAT and thoracic PVAT lead to hyperlipidaemia, which contributes to atherosclerosis development. Besides, obese WAT and abdominal PVAT release pro‐inflammatory factors that further promote atherosclerosis. To discourage atherosclerosis development, strategies that reduce the release of pro‐inflammatory factors and fatty acids from WAT and abdominal PVAT, or increase combustion of fatty acids by activation of BAT and thoracic PVAT and beiging of WAT are probably most efficient. Possible therapies could include anti‐inflammatory compounds such as adiponectin and salicylates to lower inflammation, and &bgr;3‐adrenergic receptor activators to increase fatty acid combustion. Additional and more specific strategies to promote fatty acid combustion are currently subject of investigation. In conclusion, different adipose depots differentially affect atherosclerosis development, in which atherosclerosis is promoted by energy‐storing adipose depots and attenuated by energy‐combusting adipose tissue. In obesity, combining therapies that reduce inflammation and increase combustion of lipids are most conceivable to restrain atherogenesis.

Plasma cholesteryl ester transfer protein is predominantly derived from Kupffer cells

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. Microarray analysis of liver and adipose tissue biopsies, obtained from 93 obese subjects who underwent elective bariatric surgery, showed that expression of CETP is markedly higher in liver than adipose tissue. Hepatic expression of CETP correlated strongly with that of KC markers, and CETP messenger RNA and protein colocalized specifically with KCs in human liver sections. Hepatic KC content as well as hepatic CETP expression correlated strongly with plasma CETP concentration. Mechanistic and intervention studies on the role of KCs in determining the plasma CETP concentration were performed in a transgenic (Tg) mouse model expressing human CETP. Selective elimination of KCs from the liver in CETP Tg mice virtually abolished hepatic CETP expression and largely reduced plasma CETP concentration, consequently improving the lipoprotein profile. Conversely, augmentation of KCs after Bacille‐Calemette‐Guérin vaccination largely increased hepatic CETP expression and plasma CETP. Also, lipid‐lowering drugs fenofibrate and niacin reduced liver KC content, accompanied by reduced plasma CETP concentration. Conclusions: Plasma CETP is predominantly derived from KCs, and plasma CETP level predicts hepatic KC content in humans.(Hepatology 2015;62:1710–1722)

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. As prolonged cold exposure is not a realistic therapy, researchers worldwide are searching for novel ways to activate BAT and/or induce beiging of white adipose tissue. Recently, the contribution of immune cells in the regulation of brown adipocyte activity and beiging of white adipose tissue has gained increased attention, with a prominent role for eosinophils and alternatively activated macrophages. This review discusses the rediscovery of BAT, presents an overview of modes of activation and differentiation of beige and brown adipocytes, and describes the recently discovered immunological pathways that are key in mediating brown/beige adipocyte development and function. Interventions in immunological pathways harbor the potential to provide novel strategies to increase beige and brown adipose tissue activity as a therapeutic target for obesity.

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

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.

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

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.

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. These effects coincided with decreased brown adipocyte lipid content and increased nutrient uptake by BAT, confirming increased BAT activity. Consistent with these observations, GPR120 deficiency reduced expression of genes involved in nutrient handling in BAT. Stimulation of brown adipocytes in vitro with TUG‐891 acutely induced O2 consumption, through GPR120‐dependent and GPR120‐independent mechanisms. TUG‐891 not only stimulated GPR120 signaling resulting in intracellular calcium release, mitochondrial depolarization, and mitochondrial fission, but also activated UCP1. Collectively, these data suggest that activation of brown adipocytes with the GPR120 agonist TUG‐891 is a promising strategy to increase lipid combustion and reduce obesity.

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. We determined eosinophil numbers in epididymal WAT (EpAT), subcutaneous WAT (ScAT) and BAT after 1 day, 3 days or 1 week of high-fat diet (HFD) feeding in C57Bl/6 mice. One day of HFD resulted in a rapid drop in eosinophil numbers in EpAT and BAT, and after 3 days, in ScAT. In an attempt to restore this HFD-induced drop in adipose tissue eosinophils, we treated 1-week HFD-fed mice with helminth antigens from Schistosoma mansoni or Trichuris suis and evaluated whether the well-known protective metabolic effects of helminth antigens involves BAT activation or beiging. Indeed, antigens of both helminth species induced high numbers of eosinophils in EpAT, but failed to induce beiging. In ScAT, Schistosoma mansoni antigens induced mild eosinophilia, which was accompanied by slightly more beiging. No effects were observed in BAT. To study type 2 responses on brown adipocytes directly, T37i cells were stimulated with IL-4. This increased Ucp1 expression and strongly induced the production of eosinophil chemoattractant CCL11 (+26-fold), revealing that brown adipocytes themselves can attract eosinophils. Our findings indicate that helminth antigen-induced eosinophilia fails to induce profound beiging of white adipocytes.