Glucagon-Like Peptide-1 and its Analogues Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight.

Glucagon-like peptide-1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as anti-obesity strategies. Surprisingly whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the CNS. Serotonin depletion impaired the ability of exendin-4, a clinically utilized GLP-1 analogue, to reduce body weight in rats, suggesting serotonin is a critical mediator of the energy balance impact of GLP-1R activation. Serotonin turnover and expression of 5HT2A and 5HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that 5HT2A, but surprisingly not 5HT2C, receptor is critical for weight-loss, anorexia and fat mass reduction induced by central GLP-1R activation. Importantly, central 5HT2A receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase electrical activity of the DR serotonin neurons. Finally our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as new critical neural substrate for GLP-1 impact on energy homeostasis, and expands the current map of brain areas impacted by GLP-1R activation.This research was funded by the Swedish Research Council (2014-2945 and 2013-7107), Novo Nordisk Foundation Excellence project grant, Ragnar Söderberg Foundation, Harald Jeanssons Stiftelse and Greta Jeanssons Stiftelse, and Magnus Bergvalls Stiftelse

Levelling off of prevalence of obesity in the adult population of Sweden between 2000/01 and 2004/05

<p>Abstract</p> <p>Background</p> <p>The escalating global epidemic of obesity is of worldwide concern because of its association with several chronic diseases and premature mortality. Some subgroups seem to be more affected than others. The aim of this study was to examine whether the mean BMI (adjusted for age) and the prevalence of obesity (adjusted for all the explanatory variables) changed between 2000/01 and 2004/05 in different subgroups of the Swedish population.</p> <p>Methods</p> <p>This study compared two cross-sectional, nationwide random samples of persons aged 16 to 84 years: the first from 2000/01 (5515 men, 5838 women) and the second from 2004/05 (4681 men, 4821 women). After stratification by gender, a logistic regression model was applied to analyse possible changes in mean BMI and the prevalence of obesity between 2000/01 and 2004/05.</p> <p>Results</p> <p>Total mean BMI remained almost unchanged between 2000/01 and 2004/05 for both men and women. The prevalence of obesity increased slightly in both men and women, but not significantly (from 9.7 to 10.8% and from 9.6 to 10.2%, respectively). The prevalence of obesity in 2004/05 was especially high in some subgroups: men aged 45-54 (14.3%) or 55-64 (16.5%), women aged 65-74 (15.9%) or 75-84 (16.8%), men and women of middle educational level (15.6% and 14.4%, respectively), male former smokers (13.4%), and men from small towns or rural areas (13.1%).</p> <p>Conclusions</p> <p>Although the mean BMI and obesity were almost unchanged in the Swedish adult population between 2000/01 and 2004/05, obesity levels in Sweden remained unacceptably high, especially in certain subgroups. Primary and secondary intervention actions should strive to decrease the prevalence of obesity in Sweden.</p

SLC26A1 is a major determinant of sulfate homeostasis in humans

Sulfate plays a pivotal role in numerous physiological processes in the human body, including bone and cartilage health. A role of the anion transporter SLC26A1 (Sat1) for sulfate reabsorption in the kidney is supported by the observation of hyposulfatemia and hypersulfaturia in Slc26a1-knockout mice. The impact of SLC26A1 on sulfate homeostasis in humans remains to be defined. By combining clinical genetics, functional expression assays, and population exome analysis, we identify SLC26A1 as a sulfate transporter in humans and experimentally validate several loss-of-function alleles. Whole-exome sequencing from a patient presenting with painful perichondritis, hyposulfatemia, and renal sulfate wasting revealed a homozygous mutation in SLC26A1, which has not been previously described to the best of our knowledge. Whole-exome data analysis of more than 5,000 individuals confirmed that rare, putatively damaging SCL26A1 variants were significantly associated with lower plasma sulfate at the population level. Functional expression assays confirmed a substantial reduction in sulfate transport for the SLC26A1 mutation of our patient, which we consider to be novel, as well as for the additional variants detected in the population study. In conclusion, combined evidence from 3 complementary approaches supports SLC26A1 activity as a major determinant of sulfate homeostasis in humans. In view of recent evidence linking sulfate homeostasis with back pain and intervertebral disc disorder, our study identifies SLC26A1 as a potential target for modulation of musculoskeletal health

TonEBP suppresses adipogenesis and insulin sensitivity by blocking epigenetic transition of PPAR gamma 2

TonEBP is a key transcription factor in cellular adaptation to hypertonic stress, and also in macrophage activation. Since TonEBP is involved in inflammatory diseases such as rheumatoid arthritis and atherosclerosis, we asked whether TonEBP played a role in adipogenesis and insulin resistance. Here we report that TonEBP suppresses adipogenesis and insulin signaling by inhibiting expression of the key transcription factor PPAR gamma 2. TonEBP binds to the PPAR gamma 2 promoter and blocks the epigenetic transition of the locus which is required for the activation of the promoter. When TonEBP expression is reduced, the epigenetic transition and PPAR gamma 2 expression are markedly increased leading to enhanced adipogenesis and insulin response while inflammation is reduced. Thus, TonEBP is an independent determinant of adipose insulin sensitivity and inflammation. TonEBP is an attractive therapeutic target for insulin resistance in lieu of PPAR gamma agonistsopen0

Dietary differences between elderly Iranians living in Sweden and Iran a cross-sectional comparative study

<p>Abstract</p> <p>Background</p> <p>During the last decades, global migration has increased and many immigrant groups have a higher prevalence than the native born population of several cardiovascular disease risk factors, including poor dietary habits. However, it is uncertain if dietary habits in immigrant populations reflect dietary habits in their country of origin or if the current diet is a consequence of the migration and possible change of dietary habits. The aim of this study was to examine possible dietary differences between elderly Iranians living in Stockholm, Sweden with elderly Iranians living in Tehran, Iran, taking into account sex, age, marital status, and education.</p> <p>Methods</p> <p>Dietary intakes were assessed by semi - quantitative food frequency questionnaire in a cross-sectional study of 121 Iranians living in Stockholm and 52 Iranians living in Tehran, aged 60-80. Differences in dietary habits between the two groups was analysed by bootstrapped regression analyses with 1000 replications.</p> <p>Results</p> <p>Iranians living in Sweden had significantly higher intake of protein, total fat, fiber than Iranians living in Iran, but lower consumption of carbohydrates. The observed differences in intake of macronutrients were reflected in consumed amount of all food items, which were higher among Iranians living in Iran with the exception of bread and grain consumption which was lower.</p> <p>Conclusions</p> <p>There are general differences in dietary habits between Iranians living in Iran and Iranians living in Sweden. Parts of observed differences in dietary habits may reflect a favourable adoption process to the Swedish dietary habits after migration. Meanwhile other differences are point of concern in light of the high prevalence of overweight, among Iranians living in Sweden and can have unfavourable impact in particular in the context of cardiovascular health.</p

The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

Organisms have evolved to survive rigorous environments and are not prepared to thrive in a world of caloric excess and sedentary behavior. A realization that physical exercise (or lack of it) plays a pivotal role in both the pathogenesis and therapy of type 2 diabetes mellitus (t2DM) has led to the provocative concept of therapeutic exercise mimetics. A decade ago, we attempted to simulate the beneficial effects of exercise by treating t2DM patients with 3 weeks of daily hyperthermia, induced by hot tub immersion. The short-term intervention had remarkable success, with a 1 % drop in HbA1, a trend toward weight loss, and improvement in diabetic neuropathic symptoms. An explanation for the beneficial effects of exercise and hyperthermia centers upon their ability to induce the cellular stress response (the heat shock response) and restore cellular homeostasis. Impaired stress response precedes major metabolic defects associated with t2DM and may be a near seminal event in the pathogenesis of the disease, tipping the balance from health into disease. Heat shock protein inducers share metabolic pathways associated with exercise with activation of AMPK, PGC1-a, and sirtuins. Diabetic therapies that induce the stress response, whether via heat, bioactive compounds, or genetic manipulation, improve or prevent all of the morbidities and comorbidities associated with the disease. The agents reduce insulin resistance, inflammatory cytokines, visceral adiposity, and body weight while increasing mitochondrial activity, normalizing membrane structure and lipid composition, and preserving organ function. Therapies restoring the stress response can re-tip the balance from disease into health and address the multifaceted defects associated with the disease