Periodic Reporting for period 1 - GeneLifeCard (Genetic and lifestyle regulators of cardiometabolic risk in individuals gaining weight)
Período documentado: 2020-09-01 hasta 2022-08-31
Obesity it is clearly a current public health issue. The prevalence of obesity has tripled in children and adults in the last 30 years, and there are more than 50% of overweight adults in Europe. Obesity is a major risk factor for type 2 diabetes and cardiovascular disease. Even though most obese individuals have an increase disease risk, as many as 10-40% of obese individuals, often termed “metabolically healthy obese”, do not have an increased risk as compared to metabolically unhealthy individuals (see figure). We hypothesized that the expandability of subcutaneous fat may be at play in this paradox. Meaning that the ability to store fat subcutaneously may protect from fat being stored ectopically in non-adipose tissues such as visceral fat (e.g. heart and pancreas), where it leads to lipotoxic effects.
Genetic factors play an important role in the ability to expand subcutaneous fat stores and one of the main interests of this proposal is to identify genetic loci associated with higher overall body fat and fat storage on the hip, yet an improved disease risk profile for cardiometabolic conditions.
Thus, the overall objective of the present proposal is to examine whether genetic predisposition to higher fat expandability or healthier lifestyle behaviors diminishes the impact of long-term weight change on risk of cardiometabolic disease. We do this by analyzing individuals from Danish and United Kingdom prospective studies, with data available on genetics, blood markers, cardiovascular and type 2 diabetes disease occurrence and follow-up of body weight change.
The findings on the effects of genetic variation and lifestyle (i.e. physical inactivity and smoking) may improve understanding of the biological mechanisms that link adiposity to cardiometabolic health. The relevance for society will be that these findings may open new understanding for developing novel treatments with antidiabetic or anti-cardiovascular effects, but also potential public health recommendations for disease prevention.
Genetic factors play an important role in the ability to expand subcutaneous fat stores and one of the main interests of this proposal is to identify genetic loci associated with higher overall body fat and fat storage on the hip, yet an improved disease risk profile for cardiometabolic conditions.
Thus, the overall objective of the present proposal is to examine whether genetic predisposition to higher fat expandability or healthier lifestyle behaviors diminishes the impact of long-term weight change on risk of cardiometabolic disease. We do this by analyzing individuals from Danish and United Kingdom prospective studies, with data available on genetics, blood markers, cardiovascular and type 2 diabetes disease occurrence and follow-up of body weight change.
The findings on the effects of genetic variation and lifestyle (i.e. physical inactivity and smoking) may improve understanding of the biological mechanisms that link adiposity to cardiometabolic health. The relevance for society will be that these findings may open new understanding for developing novel treatments with antidiabetic or anti-cardiovascular effects, but also potential public health recommendations for disease prevention.
The worked performed so far comprehend individual level data collection, safety storage, cleaning, and variable harmonization across the different studies. Data included questionnaire, clinical, genotype and register data information. We further used publicly available genome-wide summary level data. We applied various methodological analyses in order to analyze the data and report the results to answer the research questions including, among others, various regression models, genome wide level scans, Mendelian randomization and time-to-event analysis for disease risk assessment.
We found evidence that higher physical activity and decrease sedentary time associated with lower body weight and fat percentage in general. Meaning that physical inactivity was associated with lower body weight. We further provide bidirectional evidence of causality for the association between higher sedentary time and higher adiposity. This means that decreasing sedentary time is beneficial for weight management, but also that weight loss may help reduce sedentary time, forming a reinforcing loop. However, we found no clear evidence that higher physical activity associated with improve body fat distribution, meaning that we could not explain the hypothesis that higher fat expandability was associated with a healthier lifestyle.
In relation to smoking, our findings suggested that tobacco smoking associated with higher abdominal fat and that this came at the cost of lower gluteofemoral fat. Further that the effects were coming mostly from increase abdominal visceral adipose tissue rather than subcutaneous. Thus, our findings suggest that smoking has poor fat expandability properties. Thus, we speculate that a plausible explanation for the deleterious effects from smoking on cardiometabolic diseases may be due to a decrease fat expandability.
One of the aims of this proposal was to examine whether the genetic predispositions to higher fat expandability predict a metabolically healthy obese state in middle age and whether this state was sustained after 5-year period. Our analysis in this regard was inconclusive, most likely due to low statistical power. Thus, we could not conclude that higher genetic predisposition to higher fat expandability did not associate with metabolically healthy obese.
We show that children with low body size in childhood that then have a high body size as adults had the highest risk for type 2 diabetes. As expected, high body size in adulthood was a major risk factor for cardiometabolic disease, however body size in childhood was a risk determinant for type 2 diabetes, but not for cardiovascular disease. We speculate that lean children may have an increased susceptibility for type 2 diabetes because of a limited capacity for triglyceride storage in the adipose tissue (lower fat expandability), which may lead to metabolic complications upon weight gain due to lipotoxicity in adipose tissue and systematically.
We found evidence that higher physical activity and decrease sedentary time associated with lower body weight and fat percentage in general. Meaning that physical inactivity was associated with lower body weight. We further provide bidirectional evidence of causality for the association between higher sedentary time and higher adiposity. This means that decreasing sedentary time is beneficial for weight management, but also that weight loss may help reduce sedentary time, forming a reinforcing loop. However, we found no clear evidence that higher physical activity associated with improve body fat distribution, meaning that we could not explain the hypothesis that higher fat expandability was associated with a healthier lifestyle.
In relation to smoking, our findings suggested that tobacco smoking associated with higher abdominal fat and that this came at the cost of lower gluteofemoral fat. Further that the effects were coming mostly from increase abdominal visceral adipose tissue rather than subcutaneous. Thus, our findings suggest that smoking has poor fat expandability properties. Thus, we speculate that a plausible explanation for the deleterious effects from smoking on cardiometabolic diseases may be due to a decrease fat expandability.
One of the aims of this proposal was to examine whether the genetic predispositions to higher fat expandability predict a metabolically healthy obese state in middle age and whether this state was sustained after 5-year period. Our analysis in this regard was inconclusive, most likely due to low statistical power. Thus, we could not conclude that higher genetic predisposition to higher fat expandability did not associate with metabolically healthy obese.
We show that children with low body size in childhood that then have a high body size as adults had the highest risk for type 2 diabetes. As expected, high body size in adulthood was a major risk factor for cardiometabolic disease, however body size in childhood was a risk determinant for type 2 diabetes, but not for cardiovascular disease. We speculate that lean children may have an increased susceptibility for type 2 diabetes because of a limited capacity for triglyceride storage in the adipose tissue (lower fat expandability), which may lead to metabolic complications upon weight gain due to lipotoxicity in adipose tissue and systematically.
The current project so far served the basis for one published article, one published preprint and a manuscript work in progress soon to be submitted. The findings of this project have been presented nationally and internationally at various meetings, seminar and conferences, with outreach activities via social media but also one event with a non-scientific general audience.
The exploitation of the project was not possible due to COVID-19 restrictions. However, once these results are publicly available, anyone should have access to these open access results for applicability in any setting.
This project had also an impact in my personal career, training, and expanded my network and access infrastructure. I develop further skills like leadership, project management and communication. I expanded my publication list and research credibility in the field. All these training, experiences, networking and gained knowledge made of me a senior interdisciplinary researcher and I can humbly feel ready to become an independent leader in the short future.
This project will have a biological impact in the understanding of weight change, genetic predisposition to fat expandability and cardiometabolic risk that will pave the way for future research with translation impact. Further the public health implications of childhood and adulthood body size change in relation to the risk of cardiometabolic disease will be of relevance for disease prevention.
The exploitation of the project was not possible due to COVID-19 restrictions. However, once these results are publicly available, anyone should have access to these open access results for applicability in any setting.
This project had also an impact in my personal career, training, and expanded my network and access infrastructure. I develop further skills like leadership, project management and communication. I expanded my publication list and research credibility in the field. All these training, experiences, networking and gained knowledge made of me a senior interdisciplinary researcher and I can humbly feel ready to become an independent leader in the short future.
This project will have a biological impact in the understanding of weight change, genetic predisposition to fat expandability and cardiometabolic risk that will pave the way for future research with translation impact. Further the public health implications of childhood and adulthood body size change in relation to the risk of cardiometabolic disease will be of relevance for disease prevention.