Aging Changes the Efficacy of Central Urocortin 2 to Induce Weight Loss in Rats.

Middle-aged obesity and aging cachexia present healthcare challenges. Central responsiveness to body-weight-reducing mediators, e.g., to leptin, changes during aging in a way, which may promote middle-aged obesity and aging cachexia. Leptin is connected to urocortin 2 (Ucn2), an anorexigenic and hypermetabolic member of the corticotropin family. We aimed to study the role of Ucn2 in middle-aged obesity and aging cachexia. The food intake, body weight and hypermetabolic responses (oxygen consumption, core temperature) of male Wistar rats (3, 6, 12 and 18 months) were tested following intracerebroventricular injections of Ucn2. Following one central injection, Ucn2-induced anorexia lasted for 9 days in the 3-month, 14 days in the 6-month and 2 days in the 18-month group. Middle-aged 12-month rats failed to show anorexia or weight loss. Weight loss was transient (4 days) in the 3-month, 14 days in the 6-month and slight but long-lasting in the 18-month rats. Ucn2-induced hypermetabolism and hyperthermia increased with aging. The age-dependent changes in the mRNA expression of Ucn2 detected by RNAscope in the paraventricular nucleus correlated with the anorexigenic responsiveness. Our results show that age-dependent changes in Ucn2 may contribute to middle-aged obesity and aging cachexia. Ucn2 shows potential in the prevention of middle-aged obesity.

Maternal overnutrition elevates offspring's blood pressure-A systematic review and meta-analysis.

BACKGROUND: Maternal overnutrition during pregnancy predisposes the offspring to cardiometabolic diseases. OBJECTIVES: This systematic review and meta-analysis aimed to investigate the association between maternal overnutrition and offspring's blood pressure (BP) and the effect of offspring's obesity on this association. DATA SOURCES: PubMed, EMBASE, Clinicaltrials.gov, CENTRAL. STUDY SELECTION AND DATA EXTRACTION: Human studies published in English before October 2021 were identified that presented quantitative estimates of association between maternal overnutrition just before or during pregnancy and the offspring's BP. SYNTHESIS: Random-effect model with the DerSimonian and Laird weighting method was used to analyse regression coefficients or mean differences. RESULTS: After selection, 17 observational studies (140,517 mother-offspring pairs) were included. Prepregnancy body mass index (ppBMI) showed positive correlation with BP in offspring (regression coefficient for systolic: 0.38 mmHg per kg/m2 , 95% confidence interval (CI) 0.17, 0.58; diastolic: 0.10 mmHg per kg/m2 , 95% CI 0.05, 0.14). These indicate 1.9 mmHg increase in systolic and 0.5 mmHg increase in diastolic BP of offspring with every 5 kg/m2 gain in maternal ppBMI. Results on coefficients adjusted for offspring's BMI also showed association (systolic: 0.08 mmHg per kg/m2 , 95% CI 0.04, 0.11; diastolic: 0.03 mmHg per kg/m2 , 95% CI 0.01, 0.04). Independent from ppBMI, gestational weight gain (GWG) showed positive correlation with systolic BP (systolic BP: 0.05 mmHg per kg, 95% CI 0.01, 0.09), but not after adjustment for offspring's BMI. Mean systolic BP was higher in children of mothers with excessive GWG than in those of mothers with optimal GWG (difference: 0.65 mmHg, 95% CI 0.25, 1.05). CONCLUSIONS: Independent from offspring's BMI, higher prepregnancy BMI may increase the risk for hypertension in offspring. The positive association between GWG and offspring's systolic BP is indirect via offspring's obesity. Reduction in maternal obesity and treatment of obesity in children of obese mothers are needed to prevent hypertension.

Maternal overnutrition impairs offspring's insulin sensitivity: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to investigate the association between maternal overnutrition and offspring's insulin sensitivity-following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Studies published in English before April 22, 2019, were identified through searches of four medical databases. After selection, 15 studies aiming to explore the association between prepregnancy body mass index (ppBMI) or gestational weight gain (GWG) of non-diabetic mothers and their offspring's insulin sensitivity (fasting insulin or glucose level and Homeostatic Measurement Assessment for Insulin Resistance [HOMA-IR]) were included in the meta-analysis. Associations of ppBMI and GWG with offspring's insulin sensitivity were analysed by pooling regression coefficients or standardized differences in means with 95% confidence intervals (CIs). Maternal ppBMI showed significant positive correlations with the level of both fasting insulin and HOMA-IR in offspring (standardized regression coefficient for fasting insulin: 0.107, CI [0.053, 0.160], p < 0.001 and that for HOMA-IR: 0.063, CI [0.006, 0.121], p = 0.031). However, the result of the analysis on coefficients adjusted for offspring's actual anthropometry (BMI and adiposity) was not significant. Independent from ppBMI, GWG tended to show a positive correlation with insulin level, but not after adjustment for offspring's anthropometry. Offspring of mothers with excessive GWG showed significantly higher HOMA-IR than those of mothers with optimal GWG (p = 0.004). Our results demonstrate that both higher ppBMI and GWG increase the risk of offspring's insulin resistance, but the effect of ppBMI on insulin sensitivity in offspring may develop as consequence of their adiposity.

Obesity paradox in older sarcopenic adults - a delay in aging: A systematic review and meta-analysis.

The prognostic significance of obesity in sarcopenic adults is controversial. This systematic review and meta-analysis aimed to investigate the effect of additional obesity on health outcomes in sarcopenia. MEDLINE, EMBASE, Scopus and CENTRAL were systematically searched for studies to compare health outcomes of adults with sarcopenic obesity (SO) to those of sarcopenic non-obese (SNO) adults. We also considered the methods of assessing obesity. Of 15060 records screened, 65 papers were included (100612 participants). Older community-dwelling SO adults had 15% lower mortality risk than the SNO group (hazard ratio, HR: 0.85, 95% confidence interval 0.76, 0.94) even when obesity was assessed by measurement of body composition. Additionally, meta-regression analysis revealed a significant negative linear correlation between the age and the HR of all-cause mortality in SO vs. SNO community-dwelling adults, but not in severely ill patients. Compared with SNO, SO patients presented lower physical performance, higher risk for metabolic syndrome, but similar cognitive function, risk of falls and cardiovascular diseases. Age-related obesity, SO and later fat loss leading to SNO represent consecutive phases of biological aging. Additional obesity could worsen the health state in sarcopenia, but above 65 years SO represents a biologically earlier phase with longer life expectancy than SNO.

Activity of the hypothalamic neuropeptide Y increases in adult and decreases in old rats.

Middle-aged obesity and aging anorexia with muscle loss (sarcopenia) of old people present public health burden. These alterations may appear both in humans and rodents suggesting the role for regulatory alterations. Previously, we demonstrated that biphasic changes in the weight-reducing (catabolic) effects of neuropeptides of the hypothalamus-adipose tissue axis (e.g. leptin) may contribute to both trends. With regard to the anabolic effects of the hypothalamic neuropeptide Y (NPY) inhibited by leptin, we hypothesized non-linear age-related changes with shifts in the opposite directions. We investigated the orexigenic and hypometabolic effects of intracerebroventricularly administered NPY (hyperphagia induced by NPY injection or changes in food intake, body weight, heart rate, body temperature, locomotor activity during a 7-day NPY infusion), the immunoreactivity and gene expression of NPY in the hypothalamic arcuate nucleus of male Wistar rats of five age groups from young to old. The orexigenic/hypometabolic efficacy and the immunoreactivity of NPY increased in middle-aged animals preceding the peak of adiposity observed in aging rats, then decreased preceding anorexia and weight loss in old rats. These shifts may contribute to the development of both age-related obesity and aging anorexia, sarcopenia, and should be considered in future drug development targeting the NPY system.

Increased risk of adverse events in patients with low-on clopidogrel platelet reactivity after percutaneous coronary intervention: A systematic review and meta-analysis.

BACKGROUND: Clinical evidence has been controversial regarding the influence of low platelet reactivity (LPR), ischemic and bleeding outcomes among patients receiving coronary stent implantation. Hence, the present study performed a meta-analysis to systematically evaluate the significance of LPR on adverse cardiovascular events. METHODS: MEDLINE, EMBASE and CENTRAL databases were searched up to November 2020 for relevant studies including patients with acute coronary syndrome undergoing percutaneous coronary intervention. LPR was the exposed arm while the non-LPR group represented the control. The primary outcome of interest was bleeding risk including major and minor bleeding events. Secondary outcomes included all-cause mortality, repeated revascularization, nonfatal myocardial infarction, and stent thrombosis. Study-level outcomes were evaluated in random-effect models. RESULTS: A total of 20 studies with 19,064 patients were included. Pooled analysis showed that LPR was associated with an increased bleeding risk (relative risk [RR] 2.80, 95% confidence interval [CI] 1.95-4.02, p < 0.01). Patients with LPR had a lower risk of non-fatal myocardial infarction (RR 0.59, 95% CI 0.38-0.91, p < 0.05) and of serious vascular events (RR 0.50, 95% CI 0.30-0.84, p < 0.01). CONCLUSIONS: Low platelet reactivity is associated with an increased bleeding risk of patients who underwent coronary stent implantation. The results suggest possible benefits of this marker in risk stratification, with potential improvement in risk prediction. There are potential advantages using combinations with other factors in prediction models, however, they require further study. PROSPERO registration number: CRD42019136393).

Assessment of clinical data on urocortins and their therapeutic potential in cardiovascular diseases: A systematic review and meta-analysis.

Heart failure (HF) and cardiovascular diseases present public health challenges. Although great progress was achieved in their treatment, there is continuous need for new therapies. Urocortins of the corticotropin neuropeptide family were reported to exert beneficial effects in animal models of HF and cardiovascular diseases. We aimed to assess the available clinical evidence on the potential role of urocortins in HF and other cardiovascular diseases. We explored MEDLINE, Embase, CENTRAL, and Scopus databases. Twenty-seven studies were included in the qualitative and 15 studies (2005 patients) in the quantitative syntheses. Available data allowed us to meta-analyze the blood pressure (BP) lowering and heart rate (HR) increasing effects of urocortin 2 in HF with reduced ejection fraction. We applied meta-regression to explore the association between left ventricular ejection fraction and serum urocortin 1 and urocortin 2 levels. Short-term urocortin 2 infusion decreased mean arterial pressure in chronic HF with reduced ejection fraction (mean difference = -9.161 mmHg, 95% confidence interval [CI] -12.661 to -5.660 mmHg, p < 0.001). Such infusions increased HR mildly (mean difference = 5.629 beats/min, 95% CI 1.612 to 9.646 beats/min, p = 0.006). Although some studies reported increased urocortin 1 and urocortin 2 levels in HF with growing severity, our meta-regressions failed to confirm associations between blood urocortin levels and left ventricular ejection fraction. Clinical evidence confirms short-term BP lowering effects of urocortin 2, whereas individual studies report additional beneficial effects. Further clinical investigations are necessary to confirm the latter and the long-term value of these peptides in cardiovascular diseases. Review protocol: CRD42020163203.