Leptin production capacity determines food intake and susceptibility to obesity-induced diabetes in Oikawa–Nagao Diabetes-Prone and Diabetes-Resistant mice
瘦素生产能力决定 Oikawa-Nagao 糖尿病易感和糖尿病抵抗小鼠的食物摄入和肥胖诱导的糖尿病易感性
- 作者列表："Asai, Akira","Nagao, Mototsugu","Hayakawa, Koji","Miyazawa, Teruo","Sugihara, Hitoshi","Oikawa, Shinichi
Aims/hypothesis Obesity caused by overeating plays a pivotal role in the development of type 2 diabetes. However, it remains poorly understood how individual meal size differences are determined before the development of obesity. Here, we investigated the underlying mechanisms in determining spontaneous food intake in newly established Oikawa–Nagao Diabetes-Prone (ON-DP) and Diabetes-Resistant (ON-DR) mice. Methods Food intake and metabolic phenotypes of ON-DP and ON-DR mice under high-fat-diet feeding were compared from 5 weeks to 10 weeks of age. Differences in leptin status at 5 weeks of age were assessed between the two mouse lines. Adipose tissue explant culture was also performed to evaluate leptin production capacity in vitro. Results ON-DP mice showed spontaneous overfeeding compared with ON-DR mice. Excessive body weight gain and fat accumulation in ON-DP mice were completely suppressed to the levels seen in ON-DR mice by pair-feeding with ON-DR mice. Deterioration of glucose tolerance in ON-DP mice was also ameliorated under the pair-feeding conditions. While no differences were seen in body weight and adipose tissue mass when comparing the two mouse lines at 5 weeks of age, the ON-DP mice had lower plasma leptin concentrations and adipose tissue leptin gene expression levels. In accordance with peripheral leptin status, ON-DP mice displayed lower anorexigenic leptin signalling in the hypothalamic arcuate nucleus when compared with ON-DR mice without apparent leptin resistance. Explant culture studies revealed that ON-DP mice had lower leptin production capacity in adipose tissue. ON-DP mice also displayed higher DNA methylation levels in the leptin gene promoter region of adipocytes when compared with ON-DR mice. Conclusions/interpretation The results suggest that heritable lower leptin production capacity plays a critical role in overfeeding-induced obesity and subsequent deterioration of glucose tolerance in ON-DP mice. Leptin production capacity in adipocytes, especially before the development of obesity, may have diagnostic potential for predicting individual risk of obesity caused by overeating and future onset of type 2 diabetes. Graphical abstract
目的/假说暴饮暴食引起的肥胖在 2 型糖尿病的发展中起着举足轻重的作用。然而，在肥胖发展之前，个体的膳食大小差异是如何确定的仍然知之甚少。在此，我们研究了确定新建立的 Oikawa-Nagao 糖尿病易感 (ON-DP) 和糖尿病抵抗 (ON-DR) 小鼠自发食物摄入的潜在机制。方法比较 5 周至 10 周龄高脂饮食喂养下 ON-DP 和 ON-DR 小鼠的摄食量和代谢表型。评估了两种小鼠品系之间 5 周龄时瘦素状态的差异。还进行了脂肪组织外植体培养，以评价体外瘦素产生能力。结果与 ON-DR 小鼠相比，ON-DP 小鼠表现出自发性过度喂养。通过与 ON-DR 小鼠配对喂养，ON-DP 小鼠的过度体重增加和脂肪蓄积被完全抑制到 ON-DR 小鼠的水平。在配对喂养条件下，ON-DP 小鼠葡萄糖耐量的恶化也得到改善。虽然在 5 周龄时比较两种小鼠品系时，体重和脂肪组织质量没有观察到差异,ON-DP 小鼠血浆瘦素浓度和脂肪组织瘦素基因表达水平较低。根据外周瘦素状态，与无明显瘦素抵抗的 ON-DR 小鼠相比，ON-DP 小鼠在下丘脑弓状核中表现出较低的厌食性瘦素信号。外植体培养研究发现 ON-DP 小鼠脂肪组织瘦素产生能力较低。与 ON-DR 小鼠相比，ON-DP 小鼠在脂肪细胞瘦素基因启动子区也表现出更高的 DNA 甲基化水平。结论/解释结果表明，可遗传的低瘦素产生能力在过量喂养诱导的肥胖和随后的 ON-DP 小鼠糖耐量恶化中起关键作用。脂肪细胞中瘦素的产生能力，特别是在肥胖发生之前，可能具有预测个体暴饮暴食和未来 2 型糖尿病发病的肥胖风险的诊断潜力。图形抽象
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.