Publications by authors named "Patrick C N Rensen"

284 Publications

Loss of glucocorticoid rhythm induces an osteoporotic phenotype in female mice.

Aging Cell 2021 Sep 30:e13474. Epub 2021 Sep 30.

Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.

Glucocorticoid (GC)-induced osteoporosis is a widespread health problem that is accompanied with increased fracture risk. Detrimental effects of anti-inflammatory GC therapy on bone have been ascribed to the excess in GC exposure, but it is unknown whether there is also a role for disruption of the endogenous GC rhythm that is inherent to GC therapy. To investigate this, we implanted female C57Bl/6J mice with slow-release corticosterone (CORT) pellets to blunt the rhythm in CORT levels without inducing hypercortisolism. Flattening of CORT rhythm reduced cortical and trabecular bone volume and thickness, whilst bone structure was maintained in mice injected with supraphysiologic CORT at the time of their endogenous GC peak. Mechanistically, mice with a flattened CORT rhythm showed disrupted circadian gene expression patterns in bone, along with changes in circulating bone turnover markers indicative of a negative balance in bone remodelling. Indeed, double calcein labelling of bone in vivo revealed a reduced bone formation in mice with a flattened CORT rhythm. Collectively, these perturbations in bone turnover and structure decreased bone strength and stiffness, as determined by mechanical testing. In conclusion, we demonstrate for the first time that flattening of the GC rhythm disrupts the circadian clock in bone and results in an osteoporotic phenotype in mice. Our findings indicate that at least part of the fracture risk associated with GC therapy may be the consequence of a disturbed GC rhythm, rather than excess GC exposure alone, and that a dampened GC rhythm may contribute to the age-related risk of osteoporosis.
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http://dx.doi.org/10.1111/acel.13474DOI Listing
September 2021

Hematopoietic upstream stimulating factor 1 deficiency is associated with increased atherosclerosis susceptibility in LDL receptor knockout mice.

Sci Rep 2021 08 12;11(1):16419. Epub 2021 Aug 12.

Gorlaeus Laboratories, Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.

Total body upstream stimulatory factor 1 (USF1) deficiency in mice is associated with brown adipose tissue activation and a marked protection against the development of obesity and atherosclerotic lesions. Functional expression of USF1 has also been detected in monocytes and monocyte-derived macrophages. In the current study we therefore tested whether selective hematopoietic USF1 deficiency can also beneficially impact the development of atherosclerosis. For this purpose, LDL receptor knockout mice were transplanted with bone marrow from USF1 knockout mice or their wild-type littermate controls and subsequently fed a Western-type diet for 20 weeks to stimulate atherosclerotic lesion development. Strikingly, absence of USF1 function in bone marrow-derived cells was associated with exacerbated blood leukocyte (+ 100%; P < 0.01) and peritoneal leukocyte (+ 50%; P < 0.05) lipid loading and an increased atherosclerosis susceptibility (+ 31%; P < 0.05). These effects could be attributed to aggravated hyperlipidemia, i.e. higher plasma free cholesterol (+ 33%; P < 0.001) and cholesteryl esters (+ 39%; P < 0.001), and the development of hepatosteatosis. In conclusion, we have shown that hematopoietic USF1 deficiency is associated with an increased atherosclerosis susceptibility in LDL receptor knockout mice. These findings argue against a contribution of macrophage-specific USF1 deficiency to the previously described beneficial effect of total body USF1 deficiency on atherosclerosis susceptibility in mice.
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http://dx.doi.org/10.1038/s41598-021-95858-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361089PMC
August 2021

Testosterone reduces metabolic brown fat activity in male mice.

J Endocrinol 2021 Sep 3;251(1):83-96. Epub 2021 Sep 3.

Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Brown adipose tissue (BAT) burns substantial amounts of mainly lipids to produce heat. Some studies indicate that BAT activity and core body temperature are lower in males than females. Here we investigated the role of testosterone and its receptor (the androgen receptor; AR) in metabolic BAT activity in male mice. Castration, which renders mice testosterone deficient, slightly promoted the expression of thermogenic markers in BAT, decreased BAT lipid content, and increased basal lipolysis in isolated brown adipocytes. Further, castration increased the core body temperature. Triglyceride-derived fatty acid uptake, a proxy for metabolic BAT activity in vivo, was strongly increased in BAT from castrated mice (4.5-fold increase vs sham-castrated mice) and testosterone replacement reversed the castration-induced increase in metabolic BAT activity. BAT-specific AR deficiency did not mimic the castration effects in vivo and AR agonist treatment did not diminish the activity of cultured brown adipocytes in vitro, suggesting that androgens do not modulate BAT activity via a direct, AR-mediated pathway. In conclusion, testosterone is a negative regulator of metabolic BAT activity in male mice. Our findings provide new insight into the metabolic actions of testosterone.
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http://dx.doi.org/10.1530/JOE-20-0263DOI Listing
September 2021

Response by Brunham et al to Letter Regarding Article, "Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis".

Circulation 2021 Aug 9;144(6):e122. Epub 2021 Aug 9.

Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada (L.R.B., M.T., J.B.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055698DOI Listing
August 2021

Estradiol-driven metabolism in transwomen associates with reduced circulating extracellular vesicle microRNA-224/452.

Eur J Endocrinol 2021 Aug 27;185(4):539-552. Epub 2021 Aug 27.

Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands.

Objective: Sex steroid hormones like estrogens have a key role in the regulation of energy homeostasis and metabolism. In transwomen, gender-affirming hormone therapy like estradiol (in combination with antiandrogenic compounds) could affect metabolism as well. Given that the underlying pathophysiological mechanisms are not fully understood, this study assessed circulating estradiol-driven microRNAs (miRs) in transwomen and their regulation of genes involved in metabolism in mice.

Methods: Following plasma miR-sequencing (seq) in a transwomen discovery (n = 20) and validation cohort (n = 30), we identified miR-224 and miR-452. Subsequent systemic silencing of these miRs in male C57Bl/6 J mice (n = 10) was followed by RNA-seq-based gene expression analysis of brown and white adipose tissue in conjunction with mechanistic studies in cultured adipocytes.

Results: Estradiol in transwomen lowered plasma miR-224 and -452 carried in extracellular vesicles (EVs) while their systemic silencing in mice and cultured adipocytes increased lipogenesis (white adipose) but reduced glucose uptake and mitochondrial respiration (brown adipose). In white and brown adipose tissue, differentially expressed (miR target) genes are associated with lipogenesis (white adipose) and mitochondrial respiration and glucose uptake (brown adipose).

Conclusion: This study identified an estradiol-drive post-transcriptional network that could potentially offer a mechanistic understanding of metabolism following gender-affirming estradiol therapy.
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http://dx.doi.org/10.1530/EJE-21-0267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436186PMC
August 2021

Elevated plasma succinate levels are linked to higher cardiovascular disease risk factors in young adults.

Cardiovasc Diabetol 2021 07 27;20(1):151. Epub 2021 Jul 27.

Department of Endocrinology and Nutrition and Research Unit, University Hospital of Tarragona Joan XXIII-Institut d ́Investigació Sanitària Pere Virgili (IISPV), Tarragona, Spain.

Background: Succinate is produced by both host and microbiota, with a key role in the interplay of immunity and metabolism and an emerging role as a biomarker for inflammatory and metabolic disorders in middle-aged adults. The relationship between plasma succinate levels and cardiovascular disease (CVD) risk in young adults is unknown.

Methods: Cross-sectional study in 100 (65% women) individuals aged 18-25 years from the ACTIvating Brown Adipose Tissue through Exercise (ACTIBATE) study cohort. CVD risk factors, body composition, dietary intake, basal metabolic rate, and cardiorespiratory fitness were assessed by routine methods. Plasma succinate was measured with an enzyme-based assay. Brown adipose tissue (BAT) was evaluated by positron emission tomography, and circulating oxylipins were assessed by targeted metabolomics. Fecal microbiota composition was analyzed in a sub-sample.

Results: Individuals with higher succinate levels had higher levels of visceral adipose tissue (VAT) mass (+ 42.5%), triglycerides (+ 63.9%), C-reactive protein (+ 124.2%), diastolic blood pressure (+ 5.5%), and pro-inflammatory omega-6 oxylipins than individuals with lower succinate levels. Succinate levels were also higher in metabolically unhealthy individuals than in healthy overweight/obese peers. Succinate levels were not associated with BAT volume or activity or with fecal microbiota composition and diversity.

Conclusions: Plasma succinate levels are linked to a specific pro-inflammatory omega-6 signature pattern and higher VAT levels, and seem to reflect the cardiovascular status of young adults.
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http://dx.doi.org/10.1186/s12933-021-01333-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314524PMC
July 2021

Four-and-a-half LIM domain protein 2 (FHL2) deficiency protects mice from diet-induced obesity and high FHL2 expression marks human obesity.

Metabolism 2021 08 11;121:154815. Epub 2021 Jun 11.

Department of Medical Biochemistry, Amsterdam UMC, Amsterdam Cardiovascular Sciences, and Amsterdam Gastroenterology, Endocrinology and Metabolism, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. Electronic address:

Objective: Four-and-a-Half-LIM-domain-protein 2 (FHL2) modulates multiple signal transduction pathways but has not been implicated in obesity or energy metabolism. In humans, methylation and expression of the FHL2 gene increases with age, and high FHL2 expression is associated with increased body weight in humans and mice. This led us to hypothesize that FHL2 is a determinant of diet-induced obesity.

Methods: FHL2-deficient (FHL2-/-) and wild type male mice were fed a high-fat diet. Metabolic phenotyping of these mice, as well as transcriptional analysis of key metabolic tissues was performed. Correlation of the expression of FHL2 and relevant genes was assessed in datasets from white adipose tissue of individuals with and without obesity.

Results: FHL2 Deficiency protects mice from high-fat diet-induced weight gain, whereas glucose handling is normal. We observed enhanced energy expenditure, which may be explained by a combination of changes in multiple tissues; mild activation of brown adipose tissue with increased fatty acid uptake, increased cardiac glucose uptake and browning of white adipose tissue. Corroborating our findings in mice, expression of FHL2 in human white adipose tissue positively correlates with obesity and negatively with expression of browning-associated genes.

Conclusion: Our results position FHL2 as a novel regulator of obesity and energy expenditure in mice and human. Given that FHL2 expression increases during aging, we now show that low FHL2 expression associates with a healthy metabolic state.
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http://dx.doi.org/10.1016/j.metabol.2021.154815DOI Listing
August 2021

Triglyceride-lowering LPL alleles combined with LDL-C-lowering alleles are associated with an additively improved lipoprotein profile.

Atherosclerosis 2021 07 9;328:144-152. Epub 2021 May 9.

Dept. Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; Dept. Internal Medicine, Div. Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.

Background And Aims: Mendelian randomization studies have shown that triglyceride (TG)- lowering lipoprotein lipase (LPL) alleles and low-density lipoprotein-cholesterol (LDL-C)-lowering alleles have independent beneficial associations on cardiovascular disease (CVD) risk. We aimed to provide further insight into this observation by applying Mendelian randomization analyses of genetically-influenced TG and LDL-C levels on plasma metabolomic profiles.

Methods: We quantified over 100 lipoprotein metabolomic measures in the Netherlands Epidemiology of Obesity (NEO) study (N = 4838) and Oxford Biobank (OBB) (N = 6999) by nuclear magnetic resonance (NMR) spectroscopy. Weighted genetic scores for TG via five LPL alleles and LDL-C via 19 alleles were calculated and dichotomized by the median, resulting in four genotype combinations of high/low TG and high/low LDL-C. We performed linear regression analyses using a two × two design with the group with genetically-influenced high TG and LDL-C as a reference.

Results: Compared to the individual groups with genetically-influenced lower TG or lower LDL-C only, the group with combined genetically-influenced lower TG and LDL-C showed an overall independent and additive pattern of changes in metabolomic measures. Over 100 measures were different (p < 1.35 × 10) compared to the reference, with effect sizes and directionality being similar in NEO and OBB. Most notably, levels of all very-low density lipoprotein (VLDL) and LDL sub-particles were lower.

Conclusions: Our findings provide evidence that TG-lowering on top of LDL-C-lowering has additive beneficial effects on the lipoprotein profile compared to TG-lowering or LDL-C-lowering only, which is in accordance with reported additive genetic effects on CVD risk reduction.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.04.015DOI Listing
July 2021

Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity.

Mol Psychiatry 2021 May 28. Epub 2021 May 28.

Department of Endocrinology and Metabolism, Amsterdam University Medical Centres (UMC), University of Amsterdam, Amsterdam, The Netherlands.

Microglia play a critical role in maintaining neural function. While microglial activity follows a circadian rhythm, it is not clear how this intrinsic clock relates to their function, especially in stimulated conditions such as in the control of systemic energy homeostasis or memory formation. In this study, we found that microglia-specific knock-down of the core clock gene, Bmal1, resulted in increased microglial phagocytosis in mice subjected to high-fat diet (HFD)-induced metabolic stress and likewise among mice engaged in critical cognitive processes. Enhanced microglial phagocytosis was associated with significant retention of pro-opiomelanocortin (POMC)-immunoreactivity in the mediobasal hypothalamus in mice on a HFD as well as the formation of mature spines in the hippocampus during the learning process. This response ultimately protected mice from HFD-induced obesity and resulted in improved performance on memory tests. We conclude that loss of the rigorous control implemented by the intrinsic clock machinery increases the extent to which microglial phagocytosis can be triggered by neighboring neurons under metabolic stress or during memory formation. Taken together, microglial responses associated with loss of Bmal1 serve to ensure a healthier microenvironment for neighboring neurons in the setting of an adaptive response. Thus, microglial Bmal1 may be an important therapeutic target for metabolic and cognitive disorders with relevance to psychiatric disease.
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http://dx.doi.org/10.1038/s41380-021-01169-zDOI Listing
May 2021

Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis.

Cell 2021 Jun 27;184(13):3502-3518.e33. Epub 2021 May 27.

Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.
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http://dx.doi.org/10.1016/j.cell.2021.04.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238500PMC
June 2021

A simplified procedure to trace triglyceride-rich lipoprotein metabolism in vivo.

Physiol Rep 2021 04;9(8):e14820

Department of Medicine, Division of Endocrinology, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.

Glycerol tri[ H]oleate and [ C]cholesteryl oleate double-labeled triglyceride-rich lipoprotein (TRL)-like particles are a well-established tool to trace the effect of lipid-modulating interventions on TRL metabolism. The routine generation of these particles involves sonication of a lipid mixture and subsequent fractionation of resulting particles into populations of different average size through density gradient ultracentrifugation. Here, we describe a simplified and more time-efficient procedure for preparing TRL-like particles without the need of fractionation. The simplified procedure shortened the preparation of particles from over 4 h to less than 2 h and generated particles with a higher yield, although with a smaller average size and more heterogeneous size distribution. In C57Bl/6J mice housed at thermoneutrality (30°C), the two preparations showed highly comparable plasma clearance and organ distribution of glycerol tri[ H]oleate-derived [ H]oleate and [ C]cholesteryl oleate, as measures of lipolysis and core remnant uptake, respectively. Upon a cold challenge (14°C), plasma clearance was accelerated due to enhanced uptake of glycerol tri[ H]oleate-derived [ H]oleate by brown adipose tissue. The simplified procedure resulted in a modestly increased particle uptake by the spleen, while uptake by other organs was comparable between the two preparations. In conclusion, the simplified procedure accelerates the preparation of TRL-like particles for tracing in vivo TRL metabolism. We anticipate that this time-efficient procedure will be useful for incorporation of PET-traceable lipids to obtain more insight into human lipoprotein metabolism.
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http://dx.doi.org/10.14814/phy2.14820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095365PMC
April 2021

Circadian control of brown adipose tissue.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 08 30;1866(8):158961. Epub 2021 Apr 30.

Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Disruption of circadian (~24 h) rhythms is associated with an increased risk of cardiometabolic diseases. Therefore, unravelling how circadian rhythms are regulated in different metabolic tissues has become a prominent research focus. Of particular interest is brown adipose tissue (BAT), which combusts triglyceride-derived fatty acids and glucose into heat and displays a circannual and diurnal rhythm in its thermogenic activity. In this review, the genetic, neuronal and endocrine generation of these rhythms in BAT is discussed. In addition, the potential risks of disruption or attenuation of these rhythms in BAT, and possible factors influencing these rhythms, are addressed.
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http://dx.doi.org/10.1016/j.bbalip.2021.158961DOI Listing
August 2021

A hierarchical dynamic model used for investigating feed efficiency and its relationship with hepatic gene expression in APOE*3-Leiden.CETP mice.

Physiol Rep 2021 04;9(8):e14832

Department of Experimental Vascular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: Feed efficiency (FE) is an important trait for livestock and humans. While the livestock industry focuses on increasing FE, in the current obesogenic society it is more of interest to decrease FE. Hence, understanding mechanisms involved in the regulation of FE and particularly how it can be decreased would help tremendously in counteracting the obesity pandemic. However, it is difficult to accurately measure or calculate FE in humans. In this study, we aimed to address this challenge by developing a hierarchical dynamic model based on humanized mouse data.

Methods: We analyzed existing experimental data derived from 105 APOE*3-Leiden.CETP (E3L.CETP) mice fed a high-fat high-cholesterol (HFHC) diet for 1 (N = 20), 2 (N = 19), 3 (N = 20), and 6 (N = 46) month. We developed an ordinary differential equation (ODE) based model to estimate the FE based on the longitudinal data of body weight and food intake. Since the liver plays an important role in maintaining metabolic homeostasis, we evaluated associations between FE and hepatic gene expression levels. Depending on the feeding duration, we observed different relationships between FE and hepatic gene expression levels.

Results: After 1-month feeding of HFHC diet, we observed that FE was associated with vitamin A metabolism, arachidonic acid metabolism, and the PPAR signaling pathway. After 3- and 6-month feeding of HFHC diet, we observed that FE was associated most strongly with expression levels of Spink1 and H19, genes involved in cell proliferation and glucose metabolism, respectively.

Conclusions: In conclusion, our analysis suggests that various biological processes such as vitamin A metabolism, hepatic response to inflammation, and cell proliferation associate with FE at different stages of diet-induced obesity.
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http://dx.doi.org/10.14814/phy2.14832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087979PMC
April 2021

Common Genetic Variation in MC4R Does Not Affect Atherosclerotic Plaque Phenotypes and Cardiovascular Disease Outcomes.

J Clin Med 2021 Mar 1;10(5). Epub 2021 Mar 1.

Department Medicine, Division Endocrinology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

We analyzed the effects of the common BMI-increasing melanocortin 4 receptor (MC4R) rs17782313-C allele with a minor allele frequency of 0.22-0.25 on (1) cardiovascular disease outcomes in two large population-based cohorts (Copenhagen City Heart Study and Copenhagen General Population Study, = 106,018; and UK Biobank, = 357,426) and additionally in an elderly population at risk for cardiovascular disease ( = 5241), and on (2) atherosclerotic plaque phenotypes in samples of patients who underwent endarterectomy ( = 1439). Using regression models, we additionally analyzed whether potential associations were modified by sex or explained by changes in body mass index. We confirmed the BMI-increasing effects of +0.22 kg/m per additional copy of the C allele ( < 0.001). However, we found no evidence for an association of common MC4R genetic variation with coronary artery disease (HR 1.03; 95% CI 0.99, 1.07), ischemic vascular disease (HR 1.00; 95% CI 0.98, 1.03), myocardial infarction (HR 1.01; 95% CI 0.94, 1.08 and 1.02; 0.98, 1.07) or stroke (HR 0.93; 95% CI 0.85, 1.01), nor with any atherosclerotic plaque phenotype. Thus, common MC4R genetic variation, despite increasing BMI, does not affect cardiovascular disease risk in the general population or in populations at risk for cardiovascular disease.
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http://dx.doi.org/10.3390/jcm10050932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957774PMC
March 2021

The development of novel glucocorticoid receptor antagonists: From rational chemical design to therapeutic efficacy in metabolic disease models.

Pharmacol Res 2021 06 31;168:105588. Epub 2021 Mar 31.

Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.

Glucocorticoids regulate numerous processes in human physiology, but deregulated or excessive glucocorticoid receptor (GR) signaling contributes to the development of various pathologies including metabolic syndrome. For this reason, GR antagonists have considerable therapeutic value. Yet, the only GR antagonist that is clinically approved to date - mifepristone - exhibits cross-reactivity with other nuclear steroid receptors like the progesterone receptor. In this study, we set out to identify novel selective GR antagonists by combining rational chemical design with an unbiased in vitro and in vivo screening approach. Using this pipeline, we were able to identify CORT125329 as the compound with the best overall profile from our octahydro series of novel GR antagonists, and demonstrated that CORT125329 does not exhibit cross-reactivity with the progesterone receptor. Further in vivo testing showed beneficial activities of CORT125329 in models for excessive corticosterone exposure and short- and long-term high-fat diet-induced metabolic complications. Upon CORT125329 treatment, most metabolic parameters that deteriorated upon high-fat diet feeding were similarly improved in male and female mice, confirming activity in both sexes. However, some sexually dimorphic effects were observed including male-specific antagonism of GR activity in brown adipose tissue and female-specific lipid lowering activities after short-term CORT125329 treatment. Remarkably, CORT125329 exhibits beneficial metabolic effects despite its lack of GR antagonism in white adipose tissue. Rather, we propose that CORT125329 treatment restores metabolic activity in brown adipose tissue by stimulating lipolysis, mitochondrial activity and thermogenic capacity. In summary, we have identified CORT125329 as a selective GR antagonist with strong beneficial activities in metabolic disease models, paving the way for further clinical investigation.
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http://dx.doi.org/10.1016/j.phrs.2021.105588DOI Listing
June 2021

Cannabinoid type 1 receptor inverse agonism attenuates dyslipidemia and atherosclerosis in APOE∗3-Leiden.CETP mice.

J Lipid Res 2021 Mar 23;62:100070. Epub 2021 Mar 23.

Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.

Pharmacological blockade of the cannabinoid type 1 receptor, a G protein-coupled receptor expressed in the central nervous system and various peripheral tissues, reverses diet-induced obesity and dyslipidemia through the reduction of food intake and altered nutrient partitioning. This strategy is being explored for a number of therapeutic applications; however, its potency for the treatment of atherosclerotic cardiovascular disease via improvements in lipid metabolism remains unclear. Therefore, here, we aimed to investigate whether inhibition of the endocannabinoid system can attenuate atherosclerosis development through improvement of dyslipidemia. Lean, dyslipidemic female APOE∗3-Leiden.CETP transgenic mice were fed a Western-type diet supplemented with or without the cannabinoid type 1 receptor inverse agonist rimonabant (20 mg·kg body weight day) for up to 20 weeks. Plasma lipids and bile acids were determined, and atherosclerotic lesions were scored in the aortic valve region. Rimonabant lowered plasma levels of triglyceride (TG) (-56%) and non-HDL-C (-19%) and increased HDL-C (+57%). These effects were explained by decreased VLDL-TG production (-52%) and accelerated VLDL-TG turnover accompanied by pronounced browning of white adipose tissue. In addition, rimonabant attenuated reverse cholesterol transport (-30%), increased plasma bile acid levels (+160%), and increased hepatic cholesterol accumulation (+88%). Importantly, rimonabant markedly lowered atherosclerotic lesion size (-64%), which coincided with decreased lesion severity (28% vs. 56% severe lesions) and which strongly correlated with non-HDL-C exposure (R = 0.60). Taken together, inhibition of the endocannabinoid system potently reverses dyslipidemia and prevents atherogenesis, even in the absence of obesity.
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http://dx.doi.org/10.1016/j.jlr.2021.100070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082266PMC
March 2021

Impaired Very-Low-Density Lipoprotein catabolism links hypoglycemia to hypertriglyceridemia in Glycogen Storage Disease type Ia.

J Inherit Metab Dis 2021 07 7;44(4):879-892. Epub 2021 Apr 7.

Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Prevention of hypertriglyceridemia is one of the biomedical targets in Glycogen Storage Disease type Ia (GSD Ia) patients, yet it is unclear how hypoglycemia links to plasma triglyceride (TG) levels. We analyzed whole-body TG metabolism in normoglycemic (fed) and hypoglycemic (fasted) hepatocyte-specific glucose-6-phosphatase deficient (L-G6pc ) mice. De novo fatty acid synthesis contributed substantially to hepatic TG accumulation in normoglycemic L-G6pc mice. In hypoglycemic conditions, enhanced adipose tissue lipolysis was the main driver of liver steatosis, supported by elevated free fatty acid concentrations in GSD Ia mice and GSD Ia patients. Plasma very-low-density lipoprotein (VLDL) levels were increased in GSD Ia patients and in normoglycemic L-G6pc mice, and further elevated in hypoglycemic L-G6pc mice. VLDL-TG secretion rates were doubled in normo- and hypoglycemic L-G6pc mice, while VLDL-TG catabolism was selectively inhibited in hypoglycemic L-G6pc mice. In conclusion, fasting-induced hypoglycemia in L-G6pc mice promotes adipose tissue lipolysis and arrests VLDL catabolism. This mechanism likely contributes to aggravated liver steatosis and dyslipidemia in GSD Ia patients with poor glycemic control and may explain clinical heterogeneity in hypertriglyceridemia between GSD Ia patients.
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http://dx.doi.org/10.1002/jimd.12380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360207PMC
July 2021

Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses.

BMC Med 2021 03 18;19(1):69. Epub 2021 Mar 18.

Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Background: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease.

Methods: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions.

Results: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures.

Conclusions: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.
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http://dx.doi.org/10.1186/s12916-021-01939-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971964PMC
March 2021

Pharmacological treatment with FGF21 strongly improves plasma cholesterol metabolism to reduce atherosclerosis.

Cardiovasc Res 2021 Mar 8. Epub 2021 Mar 8.

Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.

Aims: Fibroblast growth factor (FGF) 21, a key regulator of energy metabolism, is currently evaluated in humans for treatment of type 2 diabetes and nonalcoholic steatohepatitis. However, the effects of FGF21 on cardiovascular benefit, particularly on lipoprotein metabolism in relation to atherogenesis, remain elusive.

Methods And Results: Here, the role of FGF21 in lipoprotein metabolism in relation to atherosclerosis development was investigated by pharmacological administration of a half-life extended recombinant FGF21 protein to hypercholesterolemic APOE*3-Leiden.CETP mice, a well-established model mimicking atherosclerosis initiation and development in humans. FGF21 reduced plasma total cholesterol, explained by a reduction in non-HDL-cholesterol. Mechanistically, FGF21 promoted brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning, thereby enhancing the selective uptake of fatty acids from triglyceride-rich lipoproteins into BAT and into browned WAT, consequently accelerating the clearance of the cholesterol-enriched remnants by the liver. In addition, FGF21 reduced body fat, ameliorated glucose tolerance and markedly reduced hepatic steatosis, related to upregulated hepatic expression of genes involved in fatty acid oxidation and increased hepatic VLDL-triglyceride secretion. Ultimately, FGF21 largely decreased atherosclerotic lesion area, which was mainly explained by the reduction in non-HDL-cholesterol as shown by linear regression analysis, decreased lesion severity and increased atherosclerotic plaque stability index.

Conclusions: FGF21 improves hypercholesterolemia by accelerating triglyceride-rich lipoprotein turnover as a result of activating BAT and browning of WAT, thereby reducing atherosclerotic lesion severity and increasing atherosclerotic lesion stability index. We have thus provided additional support for the clinical use of FGF21 in the treatment of atherosclerotic cardiovascular disease.

Translational Perspectives: Current therapeutics do not fully block atherosclerosis development, indicating a need for additional effective therapeutics. Here, we demonstrate that pharmacological treatment with recombinant FGF21 potently protects against atherosclerosis in APOE*3-Leiden.CETP mice. Mechanistically, FGF21 reduces hypercholesterolemia by accelerating triglyceride-rich lipoprotein turnover as a result of enhancing adipose tissue thermogenesis, thereby alleviating atherosclerotic lesion formation and severity. Consistent with our animal findings, FGF21 administration in obese patients has shown to reduce several cardiovascular risk factors such as obesity and dyslipidemia. Therefore, our present results, together with available clinical data, suggest that FGF21 is a promising therapeutic for atherosclerotic diseases.
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http://dx.doi.org/10.1093/cvr/cvab076DOI Listing
March 2021

Beneficial effects of brown fat activation on top of PCSK9 inhibition with alirocumab on dyslipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice.

Pharmacol Res 2021 05 2;167:105524. Epub 2021 Mar 2.

Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, China; Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition, by increasing hepatic low density lipoprotein (LDL) receptor (LDLR) levels, has emerged as a strategy to reduce atherosclerosis by lowering circulating very low density lipoprotein (VLDL)-cholesterol. We hypothesized that the therapeutic effectiveness of PCSK9 inhibition can be increased by accelerating the generation of VLDL remnants, which typically have a high affinity for the LDLR. Therefore, we aimed to investigate whether accelerating lipolytic processing of VLDL by brown fat activation can further lower (V)LDL and reduce atherosclerosis on top of PCSK9 inhibition. APOE*3-Leiden.CETP mice were fed a Western-type diet and treated with the anti-PCSK9 antibody alirocumab or saline. After 2 weeks, both groups of mice were randomized to receive either the selective β3-adrenergic receptor (AR) agonist CL316,243 to activate brown fat or saline for 3 additional weeks to evaluate VLDL clearance or 12 additional weeks to analyze atherosclerosis development. β3-AR agonism and alirocumab combined decreased (V)LDL-cholesterol compared to alirocumab alone, which was explained by an accelerated plasma clearance of VLDL-cholesteryl esters that were mainly taken up by the liver. In addition, the combination promoted the transfer of VLDL-phospholipids to HDL to a higher extent than alirocumab alone, accompanied by higher plasma HDL-cholesterol levels and increased cholesterol efflux capacity. Consequently, combination treatment largely reduced atherosclerotic lesion area compared to vehicle. Together, β3-AR agonism enhances the lipoprotein-modulating effects of alirocumab to further improve dyslipidemia and non-significantly further attenuate atherosclerosis development. Our findings demonstrate that brown fat activation may enhance the therapeutic effects of PCSK9 inhibition in dyslipidemia.
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http://dx.doi.org/10.1016/j.phrs.2021.105524DOI Listing
May 2021

Hepatic Scavenger Receptor Class B Type 1 Knockdown Reduces Atherosclerosis and Enhances the Antiatherosclerotic Effect of Brown Fat Activation in APOE*3-Leiden.CETP Mice.

Arterioscler Thromb Vasc Biol 2021 04 11;41(4):1474-1486. Epub 2021 Feb 11.

Division of Endocrinology, Department of Medicine, Einthoven Laboratory for Experimental Vascular Medicine (E.Z., Z.L., H.N., C.L., Z.Y., J.F.P.B., KW.v.D., P.C.N.R., Y.W.), Leiden University Medical Center, The Netherlands.

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.121.315882DOI Listing
April 2021

A physiological glucocorticoid rhythm is an important regulator of brown adipose tissue function.

Mol Metab 2021 05 3;47:101179. Epub 2021 Feb 3.

Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Objective: Brown adipose tissue (BAT) displays a strong circadian rhythm in metabolic activity, but it is unclear how this rhythm is regulated. As circulating levels of corticosterone coincide with the rhythm of triglyceride-derived fatty acid (FA) uptake by BAT, we investigated whether corticosterone regulates BAT circadian rhythm.

Methods: Corticosterone levels were flattened by implanting mice with subcutaneous corticosterone-releasing pellets, resulting in constant circulating corticosterone levels.

Results: Flattened corticosterone rhythm caused a complete loss of circadian rhythm in triglyceride-derived fatty acid uptake by BAT. This effect was independent of glucocorticoid receptor expression in (brown) adipocytes and was not caused by deregulation of clock gene expression or overexposure to glucocorticoids, but rather seemed mediated by reduced sympathetic innervation of BAT. In a mouse model of hyperlipidemia and metabolic syndrome, long-term experimental flattening of corticosterone - and thus rhythm in BAT function - resulted in adiposity.

Conclusions: This study highlights that a physiological rhythm in glucocorticoids is an important regulator of BAT function and essential for the maintenance of metabolic health.
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http://dx.doi.org/10.1016/j.molmet.2021.101179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907824PMC
May 2021

Efficacy of liraglutide on glycemic endpoints in people of Western European and South Asian descent with T2DM using multiple daily insulin injections: results of the MAGNA VICTORIA studies.

Acta Diabetol 2021 Apr 5;58(4):485-493. Epub 2021 Jan 5.

Department of Radiology, Leiden University Medical Center, LUMC Postzone C2S, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Aims: Data on the effect of liraglutide on glycemic endpoints in people with T2DM using multiple daily insulin injections (MDI) are scarce, especially in the context of ethnicity.

Methods: This is a secondary analysis of the placebo-controlled randomized clinical "MAGNA VICTORIA" trials in Western European (WE) and South Asian (SA) people with T2DM. Participants had inadequate glycemic control despite using metformin and/or sulfonylurea derivatives and/or insulin. Participants were assigned to liraglutide (1.8 mg) or placebo for 6 months, in addition to standard care. The primary endpoint number of participants reaching target HbA1c was compared for liraglutide versus placebo in the complete dataset and MDI-treated participants using Chi-square test. Liraglutide's efficacy in WE and SA was compared using a generalized linear model.

Results: Forty-five subjects were randomized to liraglutide and 51 to placebo. In each group, one participant did not complete the study. Liraglutide-treated patients reached target HbA1c more frequently: 23/45 (51%) vs 11/51 (22%), relative probability 2.4 (1.3-4.3), p = 0.002. Subgroup analysis in 43 MDI participants showed that the proportion reaching target HbA1c using liraglutide was significantly higher than in placebo: 9/22 (41%) vs 1/21 (5%), p = 0.005. There was no difference between WE and SA in terms of liraglutide efficacy (p = 0.18).

Conclusions: Liraglutide treatment resulted in increased chance of reaching target HbA1c as compared to placebo. Liraglutide efficacy was sustained in participants using MDI regimens and those of SA descent. Liraglutide should be considered for T2DM people with inadequate glycemic control despite MDI.
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http://dx.doi.org/10.1007/s00592-020-01635-0DOI Listing
April 2021

Deficiency of the Circadian Clock Gene Reduces Microglial Immunometabolism.

Front Immunol 2020 8;11:586399. Epub 2020 Dec 8.

Department of Endocrinology and Metabolism, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands.

Microglia are brain immune cells responsible for immune surveillance. Microglial activation is, however, closely associated with neuroinflammation, neurodegeneration, and obesity. Therefore, it is critical that microglial immune response appropriately adapts to different stressors. The circadian clock controls the cellular process that involves the regulation of inflammation and energy hemostasis. Here, we observed a significant circadian variation in the expression of markers related to inflammation, nutrient utilization, and antioxidation in microglial cells isolated from mice. Furthermore, we found that the core clock gene-Brain and Muscle Arnt-like 1 () plays a role in regulating microglial immune function in mice and microglial BV-2 cells by using quantitative RT-PCR. deficiency decreased gene expression of pro-inflammatory cytokines, increased gene expression of antioxidative and anti-inflammatory factors in microglia. These changes were also observed in knock-down microglial BV-2 cells under lipopolysaccharide (LPS) and palmitic acid stimulations. Moreover, Bmal1 deficiency affected the expression of metabolic associated genes and metabolic processes, and increased phagocytic capacity in microglia. These findings suggest that is a key regulator in microglial immune response and cellular metabolism.
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http://dx.doi.org/10.3389/fimmu.2020.586399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753637PMC
June 2021

Inhibition of Cholesteryl Ester Transfer Protein Preserves High-Density Lipoprotein Cholesterol and Improves Survival in Sepsis.

Circulation 2021 Mar 24;143(9):921-934. Epub 2020 Nov 24.

Centre for Heart Lung Innovation (M.T., T.P., L.B., H.J.K., J.A.R., K.R.W., J.H.B., L.R.B.), University of British Columbia, Vancouver, Canada.

Background: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis.

Methods: We examined the effect of a gain-of-function variant in (rs1800777, p.Arg468Gln) and a genetic score for decreased function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul's Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis.

Results: A fixed-effect meta-analysis of all 7 cohorts found that the gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; <0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank =0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express (50.0% versus 42.9%, Log-rank =0.87).

Conclusions: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048568DOI Listing
March 2021

Editorial: Current Challenges for Targeting Brown Fat Thermogenesis to Combat Obesity.

Front Endocrinol (Lausanne) 2020 27;11:600341. Epub 2020 Oct 27.

Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, Netherlands.

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http://dx.doi.org/10.3389/fendo.2020.600341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653195PMC
May 2021

Time for Novel Strategies to Mitigate Cardiometabolic Risk in Shift Workers.

Trends Endocrinol Metab 2020 12 9;31(12):952-964. Epub 2020 Nov 9.

Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Albinusdreef 2, 2333ZA Leiden, The Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Albinusdreef 2, 2333ZA Leiden, The Netherlands. Electronic address:

Circadian disruption induced by shift work is robustly associated with obesity, diabetes, and cardiovascular disease in humans. Less well-known are the mechanisms underlying these associations, and the effectiveness of strategies to reduce cardiometabolic risk in the shift work population. In this review, the different ways in which shift work can deteriorate cardiometabolic health, and how to use this information to reflect on various risk-mitigating strategies, is discussed. While individual strategies appear promising in animal studies, the multifactorial disease risk in shift workers likely requires a multidisciplinary approach. Therefore, the need for individually-tailored combined lifestyle interventions, that could be essential in reducing cardiometabolic disorders in the large population of shift workers in our 24/7 society, is argued.
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http://dx.doi.org/10.1016/j.tem.2020.10.005DOI Listing
December 2020

Electrical Neurostimulation Promotes Brown Adipose Tissue Thermogenesis.

Front Endocrinol (Lausanne) 2020 30;11:567545. Epub 2020 Sep 30.

Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, Netherlands.

Background: Brown adipose tissue (BAT) is present in humans and rodents, and contributes to energy expenditure by converting energy stored in lipids and glucose into heat. Beta adrenergic receptor (β-AR) agonists have been proposed as pharmacological tools to activate BAT, but they lack selectivity for this tissue. This study aimed to investigate the possibility to apply electrical neurostimulation as a novel approach to activate BAT by promoting the sympathetic outflow towards BAT.

Methods: Male C57BL/6J mice were treated with either unilateral electrical neurostimulation of interscapular BAT or with the β3-AR agonist CL316,243. Thermogenesis, nutrient uptake by BAT and downstream signaling of adrenergic receptors in BAT were examined.

Results: Electrical neurostimulation and β3-AR agonism acutely increased heat production by BAT, as evidenced by an increase in local temperature in BAT, without influencing the core body temperature. Both treatments acutely increased tyrosine hydroxylase content in the nerve terminals thereby confirming enhanced sympathetic activity. In addition, we identified increased phosphorylation of hormone-sensitive lipase coinciding with reduced intracellular lipids in BAT, without affecting acute nutrient uptake from plasma. The increased BAT temperature as induced by electrical neurostimulation was reversed by β3-AR antagonism.

Conclusion: Electrical neurostimulation acutely promotes thermogenesis in BAT as dependent on β3-AR signaling. We anticipate that electrical neurostimulation may be further developed as a novel strategy to activate BAT and thereby combat (cardio)metabolic diseases.
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http://dx.doi.org/10.3389/fendo.2020.567545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555256PMC
May 2021

How the COVID-19 pandemic highlights the necessity of animal research.

Curr Biol 2020 09 10;30(18):R1014-R1018. Epub 2020 Aug 10.

Maastricht University, 6211 LK Maastricht, The Netherlands.

Recently, a petition was offered to the European Commission calling for an immediate ban on animal testing. Although a Europe-wide moratorium on the use of animals in science is not yet possible, there has been a push by the non-scientific community and politicians for a rapid transition to animal-free innovations. Although there are benefits for both animal welfare and researchers, advances on alternative methods have not progressed enough to be able to replace animal research in the foreseeable future. This trend has led first and foremost to a substantial increase in the administrative burden and hurdles required to make timely advances in research and treatments for human and animal diseases. The current COVID-19 pandemic clearly highlights how much we actually rely on animal research. COVID-19 affects several organs and systems, and the various animal-free alternatives currently available do not come close to this complexity. In this Essay, we therefore argue that the use of animals is essential for the advancement of human and veterinary health.
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http://dx.doi.org/10.1016/j.cub.2020.08.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416712PMC
September 2020
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