Modulatory effect of methanandamide on gastric vagal afferent satiety signals depends on nutritional status.
- 作者列表："Christie S","O'Rielly R","Li H","Nunez-Salces M","Wittert GA","Page AJ
KEY POINTS:Gastric vagal afferent responses to tension are dampened in high fat diet-induced obesity. Endocannabinoids are known to dose-dependently inhibit and excite gastric vagal afferents but their effect on gastric vagal afferents in diet-induced obesity are unknown. In individual gastric vagal afferent neurons of diet-induced obese mice the co-expression of components of the endocannabinoid system, including CB1, GHSR, TRPV1, and FAAH, was increased compared to lean mice. In high fat diet-induced obese mice methanandamide only inhibited gastric vagal afferent responses to tension, possibly due to the observed change in balance of receptors, hormones, and breakdown enzymes in this system. Collectively, these data suggest endocannabinoid signalling, by gastric vagal afferents, is altered in diet-induced obesity which may impact satiety and gastrointestinal function. ABSTRACT:Gastric vagal afferents (GVAs) play a role in appetite regulation. The endocannabinoid anandamide (AEA) dose dependently inhibits and excites tension sensitive GVAs. However, it is also known that high fat diet (HFD) feeding alters GVA responses to stretch. The aim of this study was to determine the role of AEA in GVA signalling in lean and HFD-induced obese mice. Male C57BL/6 mice were fed (12wks) a standard laboratory diet (SLD) or HFD. Protein and mRNA expression of components of the cannabinoid system was determined in individual GVA cell bodies and the gastric mucosa. An in vitro GVA preparation was used to assess the effect of methanandamide (mAEA) on tension sensitive GVAs and the second messenger pathways involved. In individual GVA cell bodies, cannabinoid 1 (CB1) and ghrelin (GHSR) receptor mRNA was higher in HFD- compared to SLD-mice. Conversely, gastric mucosal AEA and ghrelin protein levels were lower in HFD- compared to SLD-mice. In SLD-mice, mAEA exerted dose-dependent inhibitory and excitatory effects on tension sensitive GVAs. Only an inhibitory effect of mAEA was observed in HFD-mice. The excitatory effect of mAEA was dependent on CB1, transient receptor potential vanilloid 1 (TRPV1) and protein kinase C. Conversely, the inhibitory effect was dependent on CB1, GHSR, TRPV1, and protein kinase A. Endocannabinoids, acting through CB1 and TRPV1, have a pivotal role in modulating GVA satiety signals depending on the second messenger pathway utilised. In HFD-mice only an inhibitory effect was observed. These changes may contribute to the development and/or maintenance of obesity. This article is protected by copyright. All rights reserved.
要点: 高脂饮食诱导的肥胖抑制了胃迷走神经传入对紧张的反应。已知内源性大麻素剂量依赖性地抑制和激发胃迷走神经传入，但其对饮食诱导肥胖中胃迷走神经传入的影响尚不清楚。在饮食诱导的肥胖小鼠的单个胃迷走神经传入神经元中，与瘦小鼠相比，内源性大麻素系统的组分，包括 CB1 、 GHSR 、 TRPV1 和 FAAH 的共表达增加。在高脂饮食诱导的肥胖小鼠中，甲酰胺仅抑制胃迷走神经传入对紧张的反应，可能是由于观察到的该系统中受体、激素和分解酶平衡的变化。总的来说，这些数据表明内源性大麻素信号，通过胃迷走神经传入，在饮食诱导的肥胖中发生改变，这可能影响饱腹感和胃肠功能。 摘要: 胃迷走神经传入 (GVAs) 在食欲调节中发挥作用。内源性大麻素 anandamide (AEA) 剂量依赖性抑制和兴奋张力敏感性 GVAs。然而，也知道高脂饮食 (HFD) 喂养会改变 GVA 对伸展的反应。本研究的目的是确定 AEA 在瘦和 HFD 诱导的肥胖小鼠 GVA 信号中的作用。雄性 C57BL/6 小鼠喂食 (12wks) 标准实验室饲料 (SLD) 或 HFD。在单个 GVA 细胞体和胃黏膜中测定大麻素系统组分的蛋白和 mRNA 表达。使用体外 GVA 制剂评估甲酰胺 (mAEA) 对张力敏感性 GVAs 和所涉及的第二信使通路的影响。在单个 GVA 细胞体中，与 SLD-小鼠相比，HFD-小鼠的大麻素 1 (CB1) 和 ghrelin (GHSR) 受体 mRNA 较高。相反，与 SLD-小鼠相比，HFD-小鼠的胃黏膜 AEA 和 ghrelin 蛋白水平较低。在 SLD-小鼠中，mAEA 对张力敏感性 GVAs 产生剂量依赖性抑制和兴奋作用。在 HFD-小鼠中仅观察到 mAEA 的抑制作用。MAEA 的兴奋作用依赖于 CB1 、瞬时受体电位香草酸 1 (TRPV1) 和蛋白激酶 C。相反，抑制作用依赖于 CB1 、 GHSR 、 TRPV1 和蛋白激酶 A。内源性大麻素通过 CB1 和 TRPV1 发挥作用，依赖于所利用的第二信使通路，在调节 GVA 饱腹感信号方面具有关键作用。在 HFD-小鼠中仅观察到抑制作用。这些变化可能有助于肥胖的发展和/或维持。本文受版权保护。保留所有权利。
METHODS:Maintaining adequate daily protein intake is important to maintain muscle mass throughout the lifespan. In this regard, the overnight period has been identified as a window of opportunity to increase protein intake in the elderly. However, it is unknown whether pre-sleep protein intake affects next-morning appetite and, consequently, protein intake. Therefore, the purpose of the current study was to investigate the effects of a pre-sleep protein drink on next-morning appetite, energy intake and metabolism. Twelve older individuals (eight males, four females; age: 71.3 ± 4.2 years) took part in a single-blind randomised cross-over study. After a standardised dinner, participants consumed either a 40-g protein drink, isocaloric maltodextrin drink, or placebo water control before bedtime. Next-morning appetite, energy intake, resting metabolic rate (RMR), respiratory exchange rate (RER), and plasma acylated ghrelin, leptin, glucose, and insulin concentrations were assessed. No between-group differences were observed for appetite and energy intake at breakfast. Furthermore, RMR, RER, and assessed blood markers were not significantly different between any of the treatment groups. Pre-sleep protein intake does not affect next-morning appetite and energy intake and is therefore a viable strategy to increase daily protein intake in an older population.
METHODS:Leptin (LEP) regulates glucose metabolism and energy storage in the body. Osteoarthritis (OA) is associated with the upregulation of serum LEP. LEP promoter methylation is associated with obesity. So far, few studies have explored the association of BMI and OA with LEP methylation. We assessed the interaction between body mass index (BMI) and OA on LEP promoter methylation. Data of 1114 participants comprising 583 men and 558 women, aged 30−70 years were retrieved from the Taiwan Biobank Database (2008−2015). Osteoarthritis was self-reported and cases were those who reported having ever been clinically diagnosed with osteoarthritis. BMI was categorized into underweight, normal weight, overweight, and obesity. The mean LEP promoter methylation level in individuals with osteoarthritis was 0.5509 ± 0.00437 and 0.5375 ± 0.00101 in those without osteoarthritis. The interaction between osteoarthritis and BMI on LEP promoter methylation was significant (p-value = 0.0180). With normal BMI as the reference, the mean LEP promoter methylation level was significantly higher in obese osteoarthritic individuals (β = 0.03696, p-value = 0.0187). However, there was no significant association between BMI and LEP promoter methylation in individuals without osteoarthritis, regardless of BMI. In conclusion, only obesity was significantly associated with LEP promoter methylation (higher levels) specifically in osteoarthritic patients.
METHODS:Background For the same BMI, South Asians have a higher body fat percentage, a higher liver fat content and a more adverse metabolic profile than whites. South Asians may have a lower fat oxidation than whites, which could result in an unfavorable metabolic profile when exposed to increased high-fat foods consumption and decreased physical activity as in current modern lifestyle. Objective To determine substrate partitioning, liver fat accumulation and metabolic profile in South Asian and white men in response to overfeeding with high-fat diet under sedentary conditions in a respiration chamber. Design Ten South Asian men (BMI, 18–29 kg/m^2) and 10 white men (BMI, 22–33 kg/m^2), matched for body fat percentage, aged 20–40 year were included. A weight maintenance diet (30% fat, 55% carbohydrate, and 15% protein) was given for 3 days. Thereafter, a baseline measurement of liver fat content (1H-MRS) and blood parameters was performed. Subsequently, subjects were overfed (150% energy requirement) with a high-fat diet (60% fat, 25% carbohydrate, and 15% protein) over 3 consecutive days while staying in a respiration chamber mimicking a sedentary lifestyle. Energy expenditure and substrate use were measured for 3 × 24-h. Liver fat and blood parameters were measured again after the subjects left the chamber. Results The 24-h fat oxidation as a percentage of total energy expenditure did not differ between ethnicities ( P = 0.30). Overfeeding increased liver fat content ( P = 0.02), but the increase did not differ between ethnicities ( P = 0.64). In South Asians, overfeeding tended to increase LDL-cholesterol ( P = 0.08), tended to decrease glucose clearance ( P = 0.06) and tended to elevate insulin response ( P = 0.07) slightly more than whites. Conclusions Despite a similar substrate partitioning and similar accretion of liver fat, overfeeding with high-fat under sedentary conditions tended to have more adverse effects on the lipid profile and insulin sensitivity in South Asians.