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Obesity increases levels of an adipocyte-produced hormone leptin, which activates the sympathetic nervous system leading to hypertension. We have recently reported that acute leptin infusion induces hypertension acting via the TRPM7 (transient receptor potential cation channel subfamily M member 7) cation channel in the carotid bodies. We hypothesize that this mechanism causes hypertension when leptin levels are elevated chronically as observed in diet-induced obesity. We have developed a novel extended release preparation, hydrogel, of a TRPM7 inhibitor FTY720, which was administered to the carotid body area bilaterally and compared with control hydrogel in (1) male lean C57BL/6J mice treated with subcutaneous infusions of leptin; (2) diet-induced obese male C57BL/6J with hyperleptinemia at baseline. In the experiment (3), diet-induced obese C57BL/6J mice, in which Trpm7 was silenced in the carotid body areas by transfection with Ad-Trpm7 shRNA , were compared with control mice transfected with Ad-CON-shRNA . All mice were implanted in the left femoral artery with telemetry before the experiments for continuous blood pressure monitoring. In lean mice, leptin increased 24 hours mean arterial pressure from 101.2±1.2 to 112±1.5 mm Hg; Trpm7 inhibitor abolished leptin-induced hypertension. Obese mice had elevated mean arterial pressure of 115.3±1.7 mm Hg, which was lowered by 8.7±1.0 mm Hg on week 2 after Trpm7 inhibitor treatment ( P Trpm7 shRNA decreased blood pressure from 119.0±2.2 to 109.6±1.4 mm Hg ( P shRNA had no effect. In conclusion, our study has shown that inhibition of TRPM7 in carotid bodies abolished leptin-induced hypertension in obese mice.

Background Obesity and its associated metabolic complications are leading causes of morbidity and mortality worldwide. Recent studies suggest that the timing of meals may be critically important for weight control and metabolic health. Consuming calories later in the day is associated with greater risks of obesity and metabolic syndrome. Interventional diet studies show more weight loss with early, rather than later, eating. Our team conducted a randomized, crossover study ("Dinner Time Study") that compared the metabolic effects of routine dinner (6pm) vs late dinner (10pm) with a fixed sleep period (11pm-7am) in young, healthy adults. We found that late dinner caused an 18% increase in post-prandial glucose and a 10% decrease in dietary fat oxidation. These metabolic consequences in the long term may lead to the development of obesity and type 2 diabetes. However, it remains unclear whether the adverse metabolic effects of late dinner are mediated by circadian misalignment (eating at the "wrong" time relative to the body's central circadian clock) or mediated by sleep (eating too close to bedtime, coinciding with the fall in metabolic rate induced by sleep). To address this question, we aim to examine the metabolic effects of early dinner, late dinner, and late dinner followed by delayed sleep, in healthy adults. Methods Dinner Time 2 Study is a randomized crossover trial with 3 treatment arms with a 3-4-week washout period: (1) early dinner + routine sleep; (2) late dinner + routine sleep; (3) late dinner + late sleep. Dinner times and bedtimes will be customized to each participant's central circadian rhythm (assessed by dim light melatonin onset, DLMO). The primary objectives of this study are to (1) examine the metabolic effects of early dinner (DLMO-3h) vs late dinner (DLMO+1h) with a fixed routine bedtime (DLMO+2h); (2) examine the metabolic effects of routine bedtime (DLMO+2h) vs delayed bedtime (DLMO+6h) with a fixed late dinner time (DLMO+1h). We will examine 24-h profiles of glucose, insulin, free fatty acids, triglycerides, and dietary fat oxidation using serial blood sampling and an ingested stable isotope ([2H31] palmitate) tracer. We aim to recruit 20 healthy adults, age 18-30 years old, with a BMI 18-29.9 kg/m2. Participants who perform night shift work or have any sleep disorders or metabolic diseases including diabetes are ineligible. Each participant will have 4 overnight admissions to our Clinical Research Unit (1 DLMO visit and 3 metabolic visits). A total of 3 participants have successfully completed the protocol since recruitment started in 2021. Conclusion Dinner Time 2 will greatly advance our understanding of the interactions between meal timing, sleep timing, and metabolism, which could inform the design and implementation of future studies that leverage chronobiology to combat diabetes and obesity. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Functionalized aromatic compounds are one of the most important light-absorbing organic chromophores - so-called brown carbon (BrC) - in fine particulate matter (PM

Daisy Duan,1 Chenjuan Gu,2 Vsevolod Y Polotsky,2 Jonathan C Jun,2 Luu V Pham2 1Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Division of Pulmonary and Critical Care, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USACorrespondence: Luu V PhamPulmonary and Critical Care Medicine, 5501 Hopkins Bayview Circle, Asthma and Allergy Center, Johns Hopkins Sleep Disorders Center, Baltimore, MD, 21224, USATel +1 410-550-0741Fax +1 410-550-3374Email luu.pham@jhmi.eduPurpose: Eating time and sleep habits are important modifiable behaviors that affect metabolic health, but the relationship between food intake and sleep remains incompletely understood. Observational data suggest that late food intake is associated with impaired sleep quality. We examined the effect of routine dinner (RD, 5 hours before bedtime) vs late dinner (LD, 1 hour before bedtime) on sleep architecture in healthy volunteers.Participants and Methods: This was a post hoc analysis of a randomized crossover study of RD vs LD with a fixed sleep opportunity in a laboratory setting. On each of the two visits, 20 healthy adult volunteers (10 women) received an isocaloric meal followed by overnight polysomnography. Sleep architecture over the course of the night was assessed using visual sleep staging and EEG spectral power analysis and was compared between RD and LD. We modeled the proportions of spectral power in alpha, beta, delta, and theta bands as functions of dinner timing, time of night, and their interaction with mixed-effect spline regression.Results: Conventional sleep stages were similar between the 2 visits. LD caused a 2.5% initial increase in delta power and a reciprocal 2.7% decrease in combined alpha and beta power (p< 0.0001). These effects diminished as sleep continued with a reversal of these patterns in the latter part of the night.Conclusion: Contrary to the existing literature, shifting dinner timing from 5 hours before sleep to 1 hour before sleep in healthy volunteers did not result in significant adverse changes in overnight sleep architecture. In fact, LD was associated with deeper sleep in the beginning of the night and lighter sleep in the latter part of the night in healthy volunteers. This novel manifestation of postprandial hypersomnia may have therapeutic potential in patients with sleep disorders.Keywords: late eating, dinner timing, sleep architecture, EEG spectral power

We have previously shown that high fat diet (HFD) for 2 weeks increases airway hyperresponsiveness (AHR) to methacholine challenge in C57BL/6J mice in association with an increase in IL-1β levels in lung tissue. We hypothesize that obesity increases AHR via the IL-1β mechanism, which can be prevented by caloric restriction and IL-1β blockade. In this study, we fed C57BL/6J mice for 8 weeks with several hypercaloric diets, including HFD, HFD supplemented with fructose, high trans-fat diet (HTFD) supplemented with fructose, either ad libitum or restricting their food intake to match body weight to the mice on a chow diet (CD). We also assessed the effect of the IL-1β receptor blocker anakinra. All mice showed the same total respiratory resistance at baseline. All obese mice showed higher AHR at 30 mg/ml of methacholine compared to CD and food restricted groups, regardless of the diet. Obese mice showed significant increases in lung IL-1 β mRNA expression, but not the protein, compared to CD and food restricted mice. Anakinra abolished an increase in AHR. We conclude that obesity leads to the airway hyperresponsiveness preventable by caloric restriction and IL-1β blockade.

Introduction Obstructive sleep apnea (OSA) has been associated with Alzheimer’s disease (AD) progression but a causal relationship is unclear. We hypothesized that OSA can influence (AD) biomarkers including beta-amyloid (Aβ) and tau, as well as neural filament light chain (NfL). Methods To test this hypothesis, we examined plasma tau, NfL, Aβ42, and Aβ40 in a randomized crossover study of OSA vs. 3-night CPAP withdrawal in 30 subjects with severe OSA adherent to CPAP. We compared the overnight change in evening to morning plasma samples across the untreated night (off) versus CPAP treated night (on). Paired t-tests were used to compare measures across sleep conditions while hierarchical linear regression with difference in the overnight change of each biomarker between conditions were set as dependent variables with age and sex as covariates. Results Of the 30 subjects, mean age was 52 years and 27% were women. As expected, CPAP withdrawal caused sleep disruption and recurrence of underlying OSA. Sleep architecture measures including %N3 (Off: 6.1% [3.7-8.5], On: 15.1% [10.6-19.6], p Conclusion This study presents some of the first evidence for an effect of acute CPAP withdrawal on neurodegenerative and amyloid plasma biomarkers and implicates a role for N3 sleep in this effect. Support (If Any) AASMF Focus award, NIDDK P30DK072488, R01AG066870, K24HL109156

BACKGROUND: Individuals with idiopathic pulmonary arterial hypertension (PAH) display reduced oral glucose tolerance. This may involve defects in pancreatic function or insulin sensitivity, but this hypothesis has not been tested; moreover, fasting nutrient metabolism remains poorly described in PAH. Thus, we aimed to characterize fasting nutrient metabolism and investigated the metabolic response to hyperglycemia in PAH. METHODS: Twelve participants (6-PAH, 6-Controls) were administered a hyperglycemic clamp, while 52 (21-PAH, 31-Controls) underwent plasma metabolomic analysis. Glucose, insulin, C-peptide, free fatty acids and acylcarnitines were assessed from the clamp. Plasma metabolomics was conducted on fasting plasma samples. RESULTS: The clamp verified a reduced insulin response to hyperglycemia in PAH (−53% vs Control), but with similar pancreatic insulin secretion. Skeletal muscle insulin sensitivity was unexpectedly greater in PAH. Hepatic insulin extraction was elevated in PAH (+11% vs Control). Plasma metabolomics identified 862 metabolites: 213 elevated, 145 reduced in PAH (p

Obstructive sleep apnea (OSA) is a breathing disorder that often coexists with visceral obesity. In this chapter, we examine bidirectional associations between obesity, OSA, and metabolic syndrome. Specifically, we will provide an overview of sleep apnea; an overview of obesity, visceral obesity, and metabolic syndrome; evidence showing that visceral obesity predisposes to OSA; evidence showing that OSA aggravates metabolic dysfunction; and clinical implications of this relationship.

[Rationale:] Obesity leads to resistant hypertension and mechanisms are poorly understood, but high plasma levels of leptin have been implicated. Leptin increases blood pressure acting both centrally in the dorsomedial hypothalamus and peripherally. Sites of the peripheral hypertensive effect of leptin have not been identified. We previously reported that leptin enhanced activity of the carotid sinus nerve, which transmits chemosensory input from the carotid bodies (CBs) to the medullary centers, and this effect was abolished by nonselective blockers of Trp (transient receptor potential) channels. We searched our mouse CB transcriptome database and found that the Trpm7 (transient receptor potential melastatin 7) channel was the most abundant Trp channel., [Objective] To examine if leptin induces hypertension acting on the CB Trpm7., [Methods and Results] C57BL/6J (n=79), leptin receptor (LepRb) deficient db/db mice (n=22), and LepRb-EGFP (n=4) mice were used. CB Trpm7 and LepRb gene expression was determined and immunohistochemistry was performed; CB glomus cells were isolated and Trpm7-like current was recorded. Blood pressure was recorded continuously in (1) leptin-treated C57BL/6J mice with intact and denervated CB; (2) leptin-treated C57BL/6J mice, which also received a nonselective Trpm7 blocker FTY720 administered systemically or topically to the CB area; (3) leptin-treated C57BL/6J mice transfected with Trpm7 small hairpin RNA to the CB, and (4) Leprb deficient obese db/db mice before and after Leprb expression in CB. Leptin receptor and Trpm7 colocalized in the CB glomus cells. Leptin induced a nonselective cation current in these cells, which was inhibited by Trpm7 blockers. Leptin induced hypertension in C57BL/6J mice, which was abolished by CB denervation, Trpm 7 blockers, and Trpm7 small hairpin RNA applied to CBs. Leprb overexpression in CB of Leprb-deficient db/db mice demethylated the Trpm7 promoter, increased Trpm7 gene expression, and induced hypertension., [Conclusions] We conclude that leptin induces hypertension acting on Trmp7 in CB, which opens horizons for new therapy.

Leptin is a potent respiratory stimulant. The carotid bodies (CB) express the long functional isoform of leptin receptor, LepRb, but the role of leptin in CB has not been fully elucidated. The objectives of the current study were (1) to examine the effect of subcutaneous leptin infusion on minute ventilation (VE) and the hypoxic ventilatory response to 10% O2 (HVR) in C57BL/6J mice before and after CB denervation; (2) to express LepRb in CB of LepRb‐deficient obese db/db mice and examine its effects on breathing during sleep and wakefulness and on HVR. We found that leptin enhanced carotid sinus nerve activity at baseline and in response to 10% O2 in vivo. In C57BL/6J mice, leptin increased VE from 1.1 to 1.5 mL/min/g during normoxia (P < 0.01) and from 3.6 to 4.7 mL/min/g during hypoxia (P < 0.001), augmenting HVR from 0.23 to 0.31 mL/min/g/Δurn:x-wiley:00223751:media:tjp13266:tjp13266-math-0001 (P < 0.001). The effects of leptin on VE and HVR were abolished by CB denervation. In db/db mice, LepRb expression in CB increased VE from 1.1 to 1.3 mL/min/g during normoxia (P < 0.05) and from 2.8 to 3.2 mL/min/g during hypoxia (P < 0.02), increasing HVR. Compared to control db/db mice, LepRb transfected mice showed significantly higher VE throughout non‐rapid eye movement (20.1 vs. −27.7 mL/min respectively, P < 0.05) and rapid eye movement sleep (16.5 vs 23.4 mL/min, P < 0.05). We conclude that leptin acts in CB to augment VE and HVR, which may protect against sleep disordered breathing in obesity., This work was funded by the NIH R01s HL133100 to V.Y.P. and J.S.K.S., R01 HL128970 to V.Y.P. and A.R.S., R01 HL138932 to V.Y.P. V.Y.P. is also supported by NIEHS grant P50 ES018176 and EPA Agreements 83615201 & 83451001. C.C.E. was supported in part by ‘Beca de estancias formativas de la Consejería de Salud de Andalucía 2017. C. Caballero Eraso. Número de expediente: EF‐0128‐2016’.

Obstructive sleep apnea (OSA) is a common sleep disorder associated with diabetes and cardiovascular disease. However, the mechanisms by which OSA causes cardiometabolic dysfunction are not fully elucidated. OSA increases plasma free fatty acids (FFA) during sleep, reflecting excessive adipose tissue lipolysis. In animal studies, intermittent hypoxia simulating OSA also increases FFA, and the increase is attenuated by beta-adrenergic blockade. In other contexts, excessive plasma FFA can lead to ectopic fat accumulation, insulin resistance, vascular dysfunction, and dyslipidemia. Herein, we propose that OSA is a cause of excessive adipose tissue lipolysis contributing towards systemic "lipotoxicity". Since visceral and upper-body obesity contributes to OSA pathogenesis, OSA-induced lipolysis may further aggravate the consequences of this metabolically harmful state. If this hypothesis is correct, then OSA may represent a reversible risk factor for cardio-metabolic dysfunction, and this risk might be mitigated by preventing OSA-induced lipolysis during sleep.

Aims Obstructive sleep apnea hypopnea syndrome (OSAHS) is associated with abnormal glucose metabolism. Nowadays, endoplasmic reticulum (ER) stress emerges as an important mechanism underlying the development of type 2 diabetes mellitus (T2DM). However, it remains unclear that intermittent hypoxia (IH) could induce ER stress, resulting in abnormality of glucose metabolism. Thus, in the current study we explore the changes of insulin signaling under IH and the role of ER stress underlying these changes. Main methods HepG2 cells were exposed to room air (RA) or IH for 8 h, 16 h and 24 h respectively. Oxygen concentration in IH groups was in a dynamic cycle from 21% to 1% every 5 min, while it remained at 21% in RA groups. Insulin was added into cell culture medium for AKT and p-AKT measurement. In another experiment set, HepG2 cells were pre-cultured with 4-PBA prior to IH or RA exposure. Expression of AKT, p-AKT, p-JNK, p-IRE1, p-PERK and p-eIF2α was examined by Western Blot. Key findings Compared with RA, p-AKT expression in HepG2 cells under IH for 24 h was significantly lower even with insulin treatment. Expression of p-JNK, p-IRE1, ATF6, p-PERK and p-eIF2α were upregulated. p-AKT level in HepG2 with 4-PBA preculture under IH was restored. p-PERK and p-eIF2α expression in HepG2 cells in IH groups with 4-PBA preculture were inhibited while levels of p-JNK and p-IRE1 remained unchanged. Significance IH, the hallmarker of OSAHS, could disturb insulin signaling via activating PERK/eIF2α.