Interaction between bone, the neuroendocrine system and metabolism

Classically, the skeleton is defined by its mechanical properties, as a site for hematopoiesis and in mineral homeostasis. In recent years, a further-reaching role has been suggested for the skeleton. In this thesis, we investigate three novel aspects of human bone metabolism. In the first part we performed a series of experiments to investigate the role of the sympathetic nervous system in human bone remodeling. There was no effect of a beta-adrenergic agonist and an antagonist on bone turnover in healthy, postmenopausal women in a randomized controlled trial. Next, we showed that bone resorption is increased in healthy volunteers receiving a selective alpha-2 adrenergic receptor agonist (clonidine). In vitro osteoclast formation and activity was not affected by clonidine. Furthermore, we did not find an association between polymorphisms in the alpha-2 adrenergic receptor and fracture risk or bone mineral density in a large international consortium. In the second part of this thesis we focused on the humoral control of bone. We described the variation in bone marrow fat during the menstrual cycle and we showed a large decrease in bone marrow fat during two weeks of estradiol treatment in postmenopausal women. In addition, we showed that an eucaloric high-fat, low-carbohydrate diet decreases, while an eucaloric low-fat, high-carbohydrate diet increases bone resorption. Finally, we investigated the role of osteocalcin, a bone-specific protein synthesized by osteoblasts, in the regulation of glucose homeostasis and testosterone levels in humans, but could not find an endocrine or metabolic role for bone

Exploring ways to make a business case for the transition towards circular business models: Making circular investment decisions in a non-circular world

A rise in global population and welfare is depleting the earth’s resources and challenging the current predominantly linear economy, following a take-make-waste pattern, calling upon a shift towards a more circular economy (Bastein and Willems, 2019; Ellen MacArthur Foundation, 2013; Lüdeke-Freund et al., 2019). The Dutch government and the European Union have set the goal/ambition to become fully circular by 2050 thus striving towards a cleaner economy and reducing the dependency on scarce resources (European Commission, 2020; Government of Netherlands, 2016)

Osteocalcin and the pituitary-gonadal axis in older men: a population-based study

Objective Osteocalcin is a well-known marker of bone formation. Recently, mice lacking osteocalcin or its receptor were reported to be subfertile with low testosterone and high luteinizing hormone concentrations. In parallel, in humans, a loss-of-function mutation of the osteocalcin receptor was associated with hypergonadotropic hypogonadism. This suggests that osteocalcin is necessary for normal pituitary-gonadal axis function. Our objective was to determine the association between physiological variations in osteocalcin and the pituitary-gonadal axis in older men. Design and patients Data were used from the Longitudinal Aging Study Amsterdam (LASA), an ongoing cohort study in a representative sample of the older Dutch population (65-88 years). Measurements Serum levels of total (T), free (FT) and bioavailable (bioT) testosterone, luteinizing hormone (LH) and osteocalcin were determined. Data were analysed using linear regression analyses and adjusted for age, BMI, 25-hydroxyvitamin D, parathyroid hormone and vitamin K antagonist use. Results A total of 614 men participated in the study. The median age was 75·4 (69·8-81·2) years, and the median osteocalcin level was 1·8 (1·3-2·4) nmol/l. Serum osteocalcin was inversely associated with FT (adjusted B = -0·22 ± 0·09 ng/dl, P = 0·012) and bioT (adjusted B = -0·26 ± 0·08 nmol/l, P < 0·01), but not with total T. Furthermore, osteocalcin was positively associated with LH (adjusted B = 0·09 ± 0·03 U/l, P < 0·01). Conclusions Serum osteocalcin was negatively associated with free and bioavailable testosterone and positively with luteinizing hormone levels

Diurnal rhythms in the white adipose tissue transcriptome are disturbed in obese individuals with type 2 diabetes compared with lean control individuals

Aims/hypothesisAnimal studies have indicated that disturbed diurnal rhythms of clock gene expression in adipose tissue can induce obesity and type 2 diabetes. The importance of the circadian timing system for energy metabolism is well established, but little is known about the diurnal regulation of (clock) gene expression in obese individuals with type 2 diabetes. In this study we aimed to identify key disturbances in the diurnal rhythms of the white adipose tissue transcriptome in obese individuals with type 2 diabetes.MethodsIn a case-control design, we included six obese individuals with type 2 diabetes and six healthy, lean control individuals. All participants were provided with three identical meals per day for 3days at zeitgeber time (ZT, with ZT 0:00 representing the time of lights on) 0:30, 6:00 and 11:30. Four sequential subcutaneous abdominal adipose tissue samples were obtained, on day 2 at ZT 15:30, and on day 3 at ZT 0:15, ZT 5:45 and ZT 11:15. Gene expression was measured using RNA sequencing.ResultsThe core clock genes showed reduced amplitude oscillations in the individuals with type 2 diabetes compared with the healthy control individuals. Moreover, in individuals with type 2 diabetes, only 1.8% (303 genes) of 16,818 expressed genes showed significant diurnal rhythmicity, compared with 8.4% (1421 genes) in healthy control individuals. Enrichment analysis revealed a loss of rhythm in individuals with type 2 diabetes of canonical metabolic pathways involved in the regulation of lipolysis. Enrichment analysis of genes with an altered mesor in individuals with type 2 diabetes showed decreased activity of the translation initiating pathway EIF2 signaling'. Individuals with type 2 diabetes showed a reduced diurnal rhythm in postprandial glucose concentrations.Conclusions/interpretationDiurnal clock and metabolic gene expression rhythms are decreased in subcutaneous adipose tissue of obese individuals with type 2 diabetes compared with lean control participants. Future investigation is needed to explore potential treatment targets as identified by our study, including clock enhancement and induction of EIF2 signalling.Data availabilityThe raw sequencing data and supplementary files for rhythmic expression analysis and Ingenuity Pathway Analysis have been deposited in NCBI Gene Expression Omnibus (GEO series accession number GSE104674).Genetics of disease, diagnosis and treatmen