Chronobiology and chronotherapy of osteoporosis

Physiological circadian (ie, 24-hour) rhythms are critical for bone health. Animal studies have shown that genes involved in the intrinsic molecular clock demonstrate potent circadian expression patterns in bone and that genetic disruption of these clock genes results in a disturbed bone structure and quality. More importantly, circulating markers of bone remodeling show diurnal variation in mice as well as humans, and circadian disruption by, eg, working night shifts is associated with the bone remodeling disorder osteoporosis. In this review, we provide an overview of the current literature on rhythmic bone remodeling and its underlying mechanisms and identify critical knowledge gaps. In addition, we discuss novel (chrono)therapeutic strategies to reduce osteoporosis by utilizing our knowledge on circadian regulation of bone. (c) 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.Diabetes mellitus: pathophysiological changes and therap

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3�6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55 of the global rise in mean BMI from 1985 to 2017�and more than 80 in some low- and middle-income regions�was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing�and in some countries reversal�of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories. © 2019, The Author(s)

Interactions between inflammation and lipid metabolism: Relevance for efficacy of anti-inflammatory drugs in the treatment of atherosclerosis

Dyslipidemia and inflammation are well known causal risk factors the development of atherosclerosis. The interplay between lipid metabolism and inflammation at multiple levels in metabolic active tissues may exacerbate the development of atherosclerosis, and will be discussed in this review. Cholesterol, fatty acids and modified lipids can directly activate inflammatory pathways. In addition, circulating (modified) lipoproteins modulate the activity of leukocytes. Vice versa, proinflammatory signaling (i.e. cytokines) in pre-clinical models directly affects lipid metabolism. Whereas the main lipid-lowering drugs all have potent anti-inflammatory actions, the lipid-modulating actions of anti-inflammatory agents appear to be less straightforward. The latter have mainly been evaluated in pre-clinical models and in patients with chronic inflammatory diseases, which will be discussed. The clinical trials that are currently conducted to evaluate the efficacy of anti-inflammatory agents in the treatment of cardiovascular diseases may additionally reveal potential (beneficial) effects of these therapeutics on lipid metabolism in the general population at risk for CVD

Inflammation increases plasma angiopoietin-like protein 4 in patients with the metabolic syndrome and type 2 diabetes

Contains fulltext : 138901.pdf (publisher's version ) (Open Access)BACKGROUND: Angiopoietin-like protein 4 (ANGPTL4) inhibits lipoprotein lipase and associates with dyslipidemia. The expression of ANGPTL4 is regulated by free fatty acids (FFA) that activate lipid-sensing peroxisome proliferator-activated receptors (PPARs), but FFA can also activate pattern recognition receptors including Toll-like receptor 4 (TLR4) in macrophages. OBJECTIVE: To assess whether systemic low-grade inflammation is a determinant for plasma ANGPTL4 levels in patients with the metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM). DESIGN: We studied 335 male participants: healthy controls (Controls), patients with the MetS without inflammation (MetS-I) and with low-grade inflammation (MetS+I), and patients with T2DM. All patients without diabetes included in the present study were initially matched for waist circumference. In plasma, ANGPTL4, C reactive protein (CRP) and metabolic parameters were determined. Underlying mechanisms were examined using human macrophages in vitro. RESULTS: As compared with Controls, plasma ANGPTL4 levels were increased in patients with MetS-I, MetS+I, and T2DM. Furthermore, ANGPTL4 was increased in T2DM compared with MetS-I. In fact, plasma CRP correlated positively with plasma ANGPTL4. In vitro studies showed that TLR 3/4 activation largely increased the expression and release of ANGPTL4 by macrophages. CONCLUSIONS: Plasma ANGPTL4 levels in humans are predicted by CRP, a marker of inflammation, and ANGPTL4 expression by macrophages is increased by inflammatory stimuli

Caloric restriction lowers endocannabinoid tonus and improves cardiac function in type 2 diabetes

Contains fulltext : 190312.pdf (publisher's version ) (Open Access

Development and preliminary evaluation of the QUALIKO: an observational quality of life instrument for patients with Korsakoff’s syndrome

Background: To develop a Korsakoff-specific measure of quality of life (QoL), to be rated by professional caregivers, and to field-test its psychometric properties in a sample of patients with Korsakoff’s syndrome (KS) living in a specialized nursing home. Methods: A research version of the QUALIKO was developed based on an existing instrument for dementia (the QUALIDEM), literature review and two rounds of surveys among expert professionals involved in the care for patients with KS. Next, QoL was independently rated using the preliminary QUALIKO for 77 patients with KS by two primary caregivers. Results: The research QUALIKO consisted of 48 items describing observable behaviors across ten aspects of QoL relevant to patients with KS. Six items demonstrated poor scalability in the field test. The remaining 42 items all formed subscales with moderate to strong scalability according to Mokken scale analysis. Reliability was acceptable to good across both raters for all subscales (Mokken rho’s = 0.70–0.90), except for the two 2-item subscales of negative affect and positive self-image (Mokken rho’s = 0.47–0.71). Inter-observer agreement was excellent for five subscales (ICCs = 0.75–0.89) and fair to moderate for the other five subscales (ICCs = 0.59–0.72). The multidimensional internal structure was confirmed and all subscales were significantly correlated with primary caregivers’ global ratings of QoL except for positive self-image. Missing item values were low and floor and ceiling effects acceptable for most subscales. Conclusions: The QUALIKO holds promise as a feasible, reliable, and valid measure of QoL in residential KS patients. Future research in larger samples is needed to confirm the psychometric dimensionality of the instrument, to gather normative data and to examine its test-retest reliability

Impact of Metformin and compound C on NIS expression and iodine uptake in vitro and in vivo: a role for CRE in AMPK modulation of thyroid function

Item does not contain fulltextBACKGROUND: Although adenosine monophosphate activated protein kinase (AMPK) plays a crucial role in energy metabolism, a direct effect of AMPK modulation on thyroid function has only recently been reported, and much of its function in the thyroid is currently unknown. The aim of this study was to investigate the mechanism of AMPK modulation in iodide uptake. Furthermore, we wanted to investigate the potential of the AMPK inhibitor compound C as an enhancer of iodide uptake by thyrocytes. METHODS: The in vitro and in vivo effects of AMPK modulation on sodium-iodide symporter (NIS) protein levels and iodide uptake were examined in follicular rat thyroid cell-line cells and C57Bl6/J mice. Activation of AMPK by metformin resulted in a strong reduction of iodide uptake (up to sixfold with 5 mM metformin after 96 h) and NIS protein levels in vitro, whereas AMPK inhibition by compound C not only stimulated iodide uptake but also enhanced NIS protein levels both in vitro (up to sevenfold with 1 muM compound C after 96 h) and in vivo (1.5-fold after daily injections with 20 mg/kg for 4 days). We investigated the regulation of NIS expression by AMPK using a range of promoter constructs consisting of either the NIS promoter or isolated CRE (cAMP response element) and NF-kappaB elements, which are present within the NIS promoter. RESULTS: Metformin reduced NIS promoter activity (0.6-fold of control), whereas compound C stimulated its activity (3.4-fold) after 4 days. This largely coincides with CRE activation (0.6- and 3.0-fold). These experiments show that AMPK exerts its effects on iodide uptake, at least partly, through the CRE element in the NIS promoter. Furthermore, we have used AMPK-alpha1 knockout mice to determine the long-term effects of AMPK inhibition without chemical compounds. These mice have a less active thyroid, as shown by reduced colloid volume and reduced responsiveness to thyrotropin. CONCLUSION: NIS expression and iodine uptake in thyrocytes can be modulated by metformin and compound C. These compounds exert their effect by modulation of AMPK, which, in turn, regulates the activation of the CRE element in the NIS promoter. Overall, this suggests that the use of AMPK modulating compounds may be useful for the enhancement of iodide uptake by thyrocytes, which could be useful for the treatment of thyroid cancer patients with radioactive iodine

Short-Term Cooling Increases Plasma ANGPTL3 and ANGPTL8 in Young Healthy Lean Men but Not in Middle-Aged Men with Overweight and Prediabetes

Angiopoietin-like proteins (ANGPTLs) regulate triglyceride (TG)-rich lipoprotein distribution via inhibiting TG hydrolysis by lipoprotein lipase in metabolic tissues. Brown adipose tissue combusts TG-derived fatty acids to enhance thermogenesis during cold exposure. It has been shown that cold exposure regulates ANGPTL4, but its effects on ANGPTL3 and ANGPTL8 in humans have not been elucidated. We therefore investigated the effect of short-term cooling on plasma ANGPTL3 and ANGPTL8, besides ANGPTL4. Twenty-four young, healthy, lean men and 20 middle-aged men with overweight and prediabetes were subjected to 2 h of mild cooling just above their individual shivering threshold. Before and after short-term cooling, plasma ANGPTL3, ANGPTL4, and ANGPTL8 were determined by ELISA. In young, healthy, lean men, short-term cooling increased plasma ANGPTL3 (+16%, p < 0.05), ANGPTL4 (+15%, p < 0.05), and ANGPTL8 levels (+28%, p < 0.001). In middle-aged men with overweight and prediabetes, short-term cooling only significantly increased plasma ANGPTL4 levels (+15%, p < 0.05), but not ANGPTL3 (230 +/- 9 vs. 251 +/- 13 ng/mL, p = 0.051) or ANGPTL8 (2.2 +/- 0.5 vs. 2.3 +/- 0.5 mu g/mL, p = 0.46). We show that short-term cooling increases plasma ANGPTL4 levels in men, regardless of age and metabolic status, but only overtly increases ANGPTL3 and ANGPTL8 levels in young, healthy, lean men.Diabetes mellitus: pathophysiological changes and therap

BMT decreases HFD-induced weight gain associated with decreased preadipocyte number and insulin secretion

Contains fulltext : 174709.pdf (publisher's version ) (Open Access)Experimental bone marrow transplantation (BMT) in mice is commonly used to assess the role of immune cell-specific genes in various pathophysiological settings. The application of BMT in obesity research is hampered by the significant reduction in high-fat diet (HFD)-induced obesity. We set out to characterize metabolic tissues that may be affected by the BMT procedure and impair the HFD-induced response. Male C57BL/6 mice underwent syngeneic BMT using lethal irradiation. After a recovery period of 8 weeks they were fed a low-fat diet (LFD) or HFD for 16 weeks. HFD-induced obesity was reduced in mice after BMT as compared to HFD-fed control mice, characterized by both a reduced fat (-33%; p<0.01) and lean (-11%; p<0.01) mass, while food intake and energy expenditure were unaffected. As compared to control mice, BMT-treated mice had a reduced mature adipocyte volume (approx. -45%; p<0.05) and reduced numbers of preadipocytes (-38%; p<0.05) and macrophages (-62%; p<0.05) in subcutaneous, gonadal and visceral white adipose tissue. In BMT-treated mice, pancreas weight (-46%; p<0.01) was disproportionally decreased. This was associated with reduced plasma insulin (-68%; p<0.05) and C-peptide (-37%; p<0.01) levels and a delayed glucose clearance in BMT-treated mice on HFD as compared to control mice. In conclusion, the reduction in HFD-induced obesity after BMT in mice is at least partly due to alterations in the adipose tissue cell pool composition as well as to a decreased pancreatic secretion of the anabolic hormone insulin. These effects should be considered when interpreting results of experimental BMT in metabolic studies