Predicting Metabolic Risk and Correlations with Cognitive Function in Mexican Pre-pubertal Children (METCOG)

BACKGROUND
Over 30% of children in Mexico and the UK are overweight/obese, with a third likely to be obese as adults. Obese individuals are more likely to develop disorders such as, high blood pressure, diabetes, increased harmful fat in the blood (dyslipidaemia), fatty liver, inflammation, heart disease and some forms of cancer. Furthermore, abdominal obesity (fat around the waist), high fat/sugar feeding as well as liver disease have been reported to lead to dysfunction in cognitive capabilities (difficulties in learning, thinking and memory). Whether the inflammation observed in obesity links the body and brain effects remains to be determined.
Body fat can be stored in specific areas, including under the skin, around certain organs as well as inside organs such as the liver. Obesity is defined the excessive build-up of body fat in these tissues. While obese individuals are more likely to be unhealthy, rather surprisingly, 1 in 5 seems to show resistance to developing clinical complications. This appears to arise from the fact that some of them may have lower amounts of fat around their abdomen. Thus, it is not only the amount but also the distribution of body fat that may better predict the risk of developing obesity-related diseases. Conventionally, a person is defined as overweight/obese by their body-mass index (BMI), skin thickness or waist-to-hip ratio. These methods are however very poor predictors of the amount and distribution of body fat. Magnetic resonance imaging (MRI) can be used to safely look into the body and can very accurately measure the amount and distribution of fat in the body as well as the amount of fat inside a person's liver. Fatty liver is often inflamed and may have fibrous deposits (fibrosis) which can exacerbate the clinical condition of an overweight/obese person. At present, little is known as to the levels and distribution of body fat in overweight/obese children as MRI techniques have not been implemented in such a group of subjects. Similarly, there is no information as to the extent to which these children have accumulated fat in their liver. Nor is there much information as to how this abnormal deposition of body fat affects their cognitive abilities.

AIMS AND OBJECTIVES
We aim to identify accurate predictors of the risk of developing physical and cognitive problems in children with a range of body weights as well as whether changes in inflammation seen in obesity links abnormal body fat deposition and changes in brain function. We will focus on pre-pubertal children to negate the varied effects of hormones during puberty on different measurements.
Objectives are to:
(1) use MRI to measure the pattern of body fat deposition in normal weight, overweight and obese children;
(2) correlate fat measures with blood levels of glucose, bad fats, molecules produced by fat cells as well as those molecules involved in inflammation;
(3) correlate different fat depots with blood inflammatory markers and liver inflammation with cognitive abilities;
(4) use experimental models of obesity (i) to determine the strength of the association between fat deposition, blood measures, blood and liver inflammation measures with brain inflammation and behaviour tests and (ii) assess whether early-life rather than later-life obesity significantly increases the risk of developing physical and cognitive dysfunction in adulthood.

POTENTIAL APPLICATIONS AND BENEFITS
The early identification of children at greater risk of future health problems enables earlier intervention which is likely to be more successful by avoiding cumulative harmful processes that may be more resistant to intervention. The obesity epidemic, alongside childhood obesity, and the ageing population, means that the outputs from this project will greatly benefit the welfare and socio-economics of Mexico and the UK, as well as the wider international community.

There is a worldwide obesity epidemic with high rates of childhood obesity. This poses a major public health challenge for both Mexico and the UK, as well as globally. Overweight/obese individuals are likely to develop a range of diseases including types II diabetes, dyslipidaemia, hepatic steatosis, coronary heart disease, some cancers, stroke, etc. This is especially pertinent to Mexico as its recent economic growth and preferred detrimental dietary habits means it has one of the highest rates of obesity (adult and children) in the OECD.

MEDICAL IMPACT
The proposal develops and validates non-invasive MRI-based tools to stratify children according to metabolic risk as well as assessment of liver fat/inflammation for prompt targeted treatment. Such tools can be readily implemented on human MRI scanners and there is widespread availability of such systems worldwide with >350 NHS scanners in the UK alone.Hence, this project can potentially have substantial medical impact both in the UK and Mexico. Without early treatment, persistent peripheral and central dysfunction may become established, leading to more severe complications and resistance to therapy in later-life. For example, fatty liver predisposes the individual to cirrhosis and liver cancer, and early treatment prevents escalation of inflamed liver to cirrhosis and hepatocellular carcinomas in later-life. The project also informs on the prevalence of fatty liver in pre-pubertal Mexican children. Such data is not widely available regarding the World's children population, let alone that of Mexico. The children study in this proposal will be performed in the Hospital Infantil del DF, Federico Gomez, and the transfer of knowledge and technology from the UK to Mexico means that the existing imaging tools can be readily deployed there in the future.
This project will uniquely determine the strength of the association between peripheral and central dysfunction in children, a relatively new research focus in obesity. Thus, knowledge will be obtained that would maintain the cognitive health of children and enhance their future prospects. In experimental models, we will determine whether inflammation connects the peripheral and central effects and anti-inflammatories repurposed for treating cognitive dysfunction in overweight/obese individuals.

SOCIO-ECONOMIC IMPACT
Not only are there direct costs of treating individuals for assorted obesity-related complications but also to the wider economy with working days lost, increased benefit payments and social care costs. Public Health England forecast NHS costs for treatment overweight/obese may be £9.7 billion and indirect costs of £49.9 billion by 2050. Also, there are adverse social consequences of being overweight/obese such as discrimination, social exclusion and loss of, or lower earnings. This project will identify those children that are at particular risk of developing obesity-related diseases to prevent them developing such diseases in later-life, enhancing their welfare but also alleviating the economic burden in their respective countries. This is particularly pertinent to Mexico as childhood obesity continues to escalate and show no signs of abating, despite government policies to tackle the problem.
Education raises productivity and creativity, promoting entrepreneurship and technological advances. Thus, if there is a strong association between childhood obesity and its complications with cognitive dysfunction, this problem needs to be addressed urgently to prevent detrimental impact on a country's economics. The project will quantify the relationship between obesity, metabolic risk and cognitive function as well as identify whether attenuating inflammation may break the link between peripheral and central dysfunction and so raise the potential of the country's children to be educated to a high standard.