Central Serotonergic Neurons Activate and Recruit Thermogenic Brown and Beige Fat and Regulate Glucose and Lipid Homeostasis

SummaryThermogenic brown and beige adipocytes convert chemical energy to heat by metabolizing glucose and lipids. Serotonin (5-HT) neurons in the CNS are essential for thermoregulation and accordingly may control metabolic activity of thermogenic fat. To test this, we generated mice in which the human diphtheria toxin receptor (DTR) was selectively expressed in central 5-HT neurons. Treatment with diphtheria toxin (DT) eliminated 5-HT neurons and caused loss of thermoregulation, brown adipose tissue (BAT) steatosis, and a >50% decrease in uncoupling protein 1 (Ucp1) expression in BAT and inguinal white adipose tissue (WAT). In parallel, blood glucose increased 3.5-fold, free fatty acids 13.4-fold, and triglycerides 6.5-fold. Similar BAT and beige fat defects occurred in Lmx1bf/fePet1Cre mice in which 5-HT neurons fail to develop in utero. We conclude 5-HT neurons play a major role in regulating glucose and lipid homeostasis, in part through recruitment and metabolic activation of brown and beige adipocytes

ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress

FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest

Objective: Excessive alcohol consumption is a leading cause of global morbidity and mortality. However, knowledge of the biological factors that influence ad libitum alcohol intake may be incomplete. Two large studies recently linked variants in the KLB locus with levels of alcohol intake in humans. KLB encodes β-klotho, co-receptor for the liver-derived hormone fibroblast growth factor 21 (FGF21). In mice, FGF21 reduces alcohol intake, and human Fgf21 variants are enriched among heavy drinkers. Thus, the liver may limit alcohol consumption by secreting FGF21. However, whether full-length, active plasma FGF21 (FGF21 (1–181)) levels in humans increase acutely or sub-chronically in response to alcohol ingestion is uncertain. Methods: We recruited 10 healthy, fasted male subjects to receive an oral water or alcohol bolus with concurrent blood sampling for FGF21 (1–181) measurement in plasma. In addition, we measured circulating FGF21 (1–181) levels, liver stiffness, triglyceride, and other metabolic parameters in three healthy Danish men before and after consuming an average of 22.6 beers/person/day (4.4 g/kg/day of ethanol) for three days during Oktoberfest 2017 in Munich, Germany. We further correlated fasting FGF21 (1–181) levels in 49 healthy, non-alcoholic subjects of mixed sex with self-reports of alcohol-related behaviors, emotional responses, and problems. Finally, we characterized the effect of recombinant human FGF21 injection on ad libitum alcohol intake in mice. Results: We show that alcohol ingestion (25.3 g or ∼2.5 standard drinks) acutely increases plasma levels of FGF21 (1–181) 3.4-fold in fasting humans. We also find that binge drinking for three days at Oktoberfest is associated with a 2.1-fold increase in baseline FGF21 (1–181) levels, in contrast to minor deteriorations in metabolic and hepatic biomarkers. However, basal FGF21 (1–181) levels were not correlated with differences in alcohol-related behaviors, emotional responses, or problems in our non-alcoholic subjects. Finally, we show that once-daily injection of recombinant human FGF21 reduces ad libitum alcohol intake by 21% in mice. Conclusions: FGF21 (1–181) is markedly increased in circulation by both acute and sub-chronic alcohol intake in humans, and reduces alcohol intake in mice. These observations are consistent with a role for FGF21 as an endocrine inhibitor of alcohol appetite in humans. Keywords: Fibroblast growth factor 21, FGF21, Alcohol, Alcohol appetit

Exercise Intensity and Duration Effects on In Vivo Immunity

PURPOSE: To examine the effects of intensity and duration of exercise stress on induction of in vivo immunity in humans using experimental contact hypersensitivity (CHS) with the novel antigen diphenylcyclopropenone (DPCP). METHODS: Sixty-four healthy males completed either 30 min running at 60% V O2peak (30MI), 30 min running at 80% V O2peak (30HI), 120 min running at 60% V O2peak (120MI), or seated rest (CON). Twenty min later, the subjects received a sensitizing dose of DPCP; and 4 wk later, the strength of immune reactivity was quantified by measuring the cutaneous responses to a low dose-series challenge with DPCP on the upper inner arm. Circulating epinephrine, norepinephrine and cortisol were measured before, after, and 1 h after exercise or CON. Next, to understand better whether the decrease in CHS response on 120MI was due to local inflammatory or T-cell-mediated processes, in a crossover design, 11 healthy males performed 120MI and CON, and cutaneous responses to a dose series of the irritant, croton oil (CO), were assessed on the upper inner arm. RESULTS: Immune induction by DPCP was impaired by 120MI (skinfold thickness -67% vs CON; P < 0.05). However, immune induction was unaffected by 30MI and 30HI despite elevated circulating catecholamines (30HI vs pre: P < 0.01) and greater circulating cortisol post 30HI (vs CON; P < 0.01). There was no effect of 120MI on skin irritant responses to CO. CONCLUSIONS: Prolonged moderate-intensity exercise, but not short-lasting high- or short-lasting moderate-intensity exercise, decreases the induction of in vivo immunity. No effect of prolonged moderate-intensity exercise on the skin's response to irritant challenge points toward a suppression of cell-mediated immunity in the observed decrease in CHS. Diphenylcyclopropenone provides an attractive tool to assess the effect of exercise on in vivo immunity

New Zealand blackcurrant extract modulates the heat shock response in men during exercise in hot ambient conditions

Purpose: To determine if 7d of New Zealand blackcurrant (NZBC) extract alters the heat shock, inflammatory and apoptotic response during prolonged exertional-heat stress. Methods: Ten men (Age: 29 ± 2 years, Stature: 1.82 ± 0.02 m, Mass: 80.3 ± 2.7 kg, V̇O2max: 56 ± 2 mL·kg−1·min−1) ingested two capsules of CurraNZ™ (NZBC extract: 210 mg anthocyanins·day−1) or PLACEBO for 7d prior to 1 h treadmill run (65% V̇O2max) in hot ambient conditions (34 °C/40% RH). Blood samples were collected before (Pre), immediately after (Post), 1 h after (1-Post), and 4 h after (4-Post) exercise. Heat shock proteins (HSP90, HSP70, HSP32) were measured in plasma. HSP and protein markers of inflammatory capacity (TLR4, NF-κB) and apoptosis (BAX/BCL-2, Caspase 9) were measured in peripheral blood mononuclear cells (PBMC). Results: eHSP32 was elevated at baseline in NZBC(+ 31%; p < 0.001). In PLACEBO HSP32 content in PBMC was elevated at 4-Post(+ 98%; p = 0.002), whereas in NZBC it fell at Post(− 45%; p = 0.030) and 1-Post(− 48%; p = 0.026). eHSP70 was increased at Post in PLACEBO(+ 55.6%, p = 0.001) and NZBC (+ 50.7%, p = 0.010). eHSP90 was increased at Post(+ 77.9%, p < 0.001) and 1-Post(+ 73.2%, p < 0.001) in PLACEBO, with similar increases being shown in NZBC (+ 49.0%, p = 0.006 and + 66.2%, p = 0.001; respectively). TLR4 and NF-κB were both elevated in NZBC at PRE(+ 54%, p = 0.003 and + 57%, p = 0.004; respectively). Main effects of study condition were also shown for BAX/BCL-2(p = 0.025) and Caspase 9 (p = 0.043); both were higher in NZBC. Conclusion: 7d of NZBC extract supplementation increased eHSP32 and PBMC HSP32 content. It also increased inflammatory and apoptotic markers in PBMC, suggesting that NZBC supports the putative inflammatory response that accompanies exertional-heat stress

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2·72 (95% uncertainty interval [UI] 2·66–2·79) in 2000 to 2·31 (2·17–2·46) in 2019. Global annual livebirths increased from 134·5 million (131·5–137·8) in 2000 to a peak of 139·6 million (133·0–146·9) in 2016. Global livebirths then declined to 135·3 million (127·2–144·1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2·1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27·1% (95% UI 26·4–27·8) of global livebirths. Global life expectancy at birth increased from 67·2 years (95% UI 66·8–67·6) in 2000 to 73·5 years (72·8–74·3) in 2019. The total number of deaths increased from 50·7 million (49·5–51·9) in 2000 to 56·5 million (53·7–59·2) in 2019. Under-5 deaths declined from 9·6 million (9·1–10·3) in 2000 to 5·0 million (4·3–6·0) in 2019. Global population increased by 25·7%, from 6·2 billion (6·0–6·3) in 2000 to 7·7 billion (7·5–8·0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58·6 years (56·1–60·8) in 2000 to 63·5 years (60·8–66·1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019