̽��ֱ�� of Cambridge - Luca Lotta

Discovery of genetic variants that protect against obesity and type 2 diabetes could lead to new weight loss medicines

cjb250 — Thu, 18 Apr 2019 15:00:18 +0000

Scientists have known for several years that genes can influence a person’s weight. One of the genes that is known to play a key role in regulating weight is MC4R, which codes for the melanocortin 4 receptor. This receptor acts like a switch in the brain to suppress appetite. People who have genetic variants that disrupt this receptor gain weight easily.

Now, in a study published today in the journal Cell, researchers have shown that other genetic variants in the MC4R gene that increase the activity of this brain receptor can protect people from becoming overweight, a finding that could lead to the development of new medicines that ‘copy’ the protective effect of these genetic variants to achieve or maintain weight-loss.

A team led by Professors Sadaf Farooqi and Nick Wareham and Dr Claudia Langenberg at the Wellcome Trust-MRC Institute of Metabolic Science in Cambridge looked at the MC4R gene in half a million volunteers from the UK population who have taken part in the UK Biobank study, finding 61 distinct naturally-occurring genetic variants. While some of these genetic variants predisposed people to become obese, other variants provided protection against obesity and some of its major complications, such as type 2 diabetes and heart disease.

To investigate the reasons for this mystery, Professor Farooqi’s team, who previously showed that MC4R works in the brain as a ‘switch’ to tell us to stop eating after a meal, studied the function of these genetic variants in a number of laboratory experiments. They found that MC4R gene variants linked to higher obesity risk stopped the gene from working, whereas variants that offered protection against obesity kept the gene ‘switched on’.

Around six per cent of study participants carried genetic variants that caused the receptor to remain ‘switched on’. People with these variants would eat less, which could explain their lower weight. People with two copies of these particular variants (1 in over 1,000 people) were on average 2.5 kg lighter than people without the variants and had a 50% lower risk of type 2 diabetes and heart disease.

“This study drives home the fact that genetics plays a major role in why some people are obese – and that some people are fortunate enough to have genes that protect them from obesity,” says Professor Farooqi of the ̽��ֱ�� of Cambridge Metabolic Research Laboratories.

̽��ֱ��discovery adds to recent work by the team which showed that some slim people have a genetic advantage when it comes to maintaining their weight.

“It doesn’t mean that we can’t influence our weight by watching what we eat, but it does mean the odds are stacked against some people and in favour of others,” added Professor Farooqi.

When the researchers looked in detail at the genetic variants in laboratory experiments, they found that MC4R can send signals through a pathway – known as the beta-arrestin pathway – that had not previously been linked to weight regulation. Genetic variants that sent signals preferentially through this pathway were the ones driving the association with protection against obesity and its complications and, importantly, were also associated with lower blood pressure. Designing drugs that mimic the effect of the protective variants in MC4R could provide new, safer weight loss therapies.

“A powerful emerging concept is that genetic variants that protect against disease can be used as models for the development of medicines that are more effective and safer,” said Dr Luca Lotta, Senior Clinical Investigator at the Medical Research Council Epidemiology Unit and joint lead author of the study. “Our findings may pave the way for a new generation of weight loss therapies that activate MC4R preferentially via the beta-arrestin pathway.”

“Our work would not have been possible without the unique blend of expertise in large-scale genetic epidemiology analysis and laboratory experiments at the Institute of Metabolic Science,” says Professor Wareham, Director of the MRC Epidemiology Unit and Co-Director of the Institute.

“Genetic studies of thousands of people and a functional understanding of the mechanisms behind protective genetic variants can really help us inform the development of a new generation of medicines for common diseases like obesity and diabetes that affect millions of people globally.”

̽��ֱ��work was funded by the MRC and Wellcome, with support from the NIHR Cambridge Biomedical Research Centre.

Reference
Lotta, LA, Mokrosiński, J et al. Human gain-of-function MC4R variants show signaling bias and protect against obesity. Cell; 18 April 2019; DOI: 10.1016/j.cell.2019.03.044

Around four million people in the UK carry genetic variants that protect them from obesity, type 2 diabetes and heart disease, suggests new research from the ̽��ֱ�� of Cambridge. ̽��ֱ��team say the discovery could lead to the development of new drugs that help people lose weight.

This study drives home the fact that genetics plays a major role in why some people are obese – and that some people are fortunate enough to have genes that protect them from obesity

Sadaf Farooqi

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Inability to safely store fat increases risk of diabetes and heart disease

cjb250 — Mon, 14 Nov 2016 16:00:21 +0000

Overeating and lack of physical activity worldwide has led to rising levels of obesity and a global epidemic of diseases such as heart disease, stroke and type 2 diabetes. A key process in the development of these diseases is the progressive resistance of the body to the actions of insulin, a hormone that controls the levels of blood sugar. When the body becomes resistant to insulin, levels of blood sugars and lipids rise, increasing the risk of diabetes and heart disease. However, it is not clear in most cases how insulin resistance arises and why some people become resistant, particularly when overweight, while others do not.

An international team led by researchers at the ̽��ֱ�� of Cambridge studied over two million genetic variants in almost 200,000 people to look for links to insulin resistance. In an article published today in Nature Genetics, they report 53 regions of the genome associated with insulin resistance and higher risk of diabetes and heart disease; only 10 of these regions have previously been linked to insulin resistance.

̽��ֱ��researchers then carried out a follow-up study with over 12,000 participants in the Fenland and EPIC-Norfolk studies, each of whom underwent a body scan that shows fat deposits in different regions of the body. They found that having a greater number of the 53 genetic variants for insulin resistance was associated with having lower amounts of fat under the skin, particularly in the lower half of the body.

̽��ֱ��team also found a link between having a higher number of the 53 genetic risk variants and a severe form of insulin resistance characterized by loss of fat tissue in the arms and legs, known as familial partial lipodystrophy type 1. Patients with lipodystrophy are unable to adequately develop fat tissue when eating too much, and often develop diabetes and heart disease as a result.

In follow-up experiments in mouse cells, the researchers were also able to show that suppression of several of the identified genes (including CCDC92, DNAH10 and L3MBTL3) results in an impaired ability to develop mature fat cells.

“Our study provides compelling evidence that a genetically-determined inability to store fat under the skin in the lower half of the body is linked to a higher risk of conditions such as diabetes and heart disease,” says Dr Luca Lotta from the Medical Research Council (MRC) Epidemiology Unit at the ̽��ֱ�� of Cambridge. “Our results highlight the important biological role of peripheral fat tissue as a deposit of the surplus of energy due to overeating and lack of physical exercise.”

“We’ve long suspected that problems with fat storage might lead to its accumulation in other organs such as the liver, pancreas and muscles, where it causes insulin resistance and eventually diabetes, but the evidence for this has mostly come from rare forms of human lipodystrophy,” adds Professor Sir Stephen O’Rahilly from the MRC Metabolic Diseases Unit and Metabolic Research Laboratories at the ̽��ֱ�� of Cambridge. “Our study suggests that these processes also take place in the general population.”

Overeating and being physically inactive leads to excess energy, which is stored as fat tissue. This new study suggests that among individuals who have similar levels of eating and physical exercise, those who are less able store the surplus energy as fat in the peripheral body, such as the legs, are at a higher risk of developing insulin resistance, diabetes and cardiovascular disease than those who are able to do so.

“People who carry the genetic risk variants that we’ve identified store less fat in peripheral areas,” says Professor Nick Wareham, also from the MRC Epidemiology Unit. “But this does not mean that they are free from risk of disease, because when their energy intake exceeds expenditure, excess fat is more likely to be stored in unhealthy deposits. ̽��ֱ��key to avoiding the adverse effects is the maintenance of energy balance by limiting energy intake and maximising expenditure through physical activity.”

These new findings may lead to future improvements in the way we prevent and treat insulin resistance and its complications. ̽��ֱ��researchers are now collaborating with other academic as well as industry partners with the aim of finding drugs that may reduce the risk of diabetes and heart attack by targeting the identified pathways.

̽��ֱ��research was mainly funded by the Medical Research Council, with additional support from the Wellcome Trust.

Reference
Lotta, LA et al. Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nature Genetics; 14 Nov 2016; DOI: 10.1038/ng.3714

A large-scale genetic study has provided strong evidence that the development of insulin resistance – a risk factor for type 2 diabetes and heart attacks and one of the key adverse consequences of obesity – results from the failure to safely store excess fat in the body.

We’ve long suspected that problems with fat storage might lead to its accumulation in other organs, where it causes insulin resistance and eventually diabetes, but the evidence for this has mostly come from rare forms of human lipodystrophy

Steve O'Rahilly

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