Obesity is not a new problem. Hippocrates described morbid obesity in the 5th century BC, including the resulting sleep apnea, infertility, and other consequences we recognize today.
“Eating behavior is not free will,” said Sadaf Farooqi, MB, ChB (Hons), PhD, who presented this year’s Outstanding Scientific Achievement Award lecture on Monday at the Scientific Sessions. “There’s an innate component that is hard wired into the brain, as well as environmental factors.”
What’s new is the growing global prevalence of obesity. But obesity is not uniform, said Dr. Farooqi, a Wellcome Trust Principal Research Fellow and Professor of Metabolism and Medicine at the Wellcome-MRC Institute of Metabolic Science, University of Cambridge, United Kingdom.
“The strong variability in obesity suggests heritability in weight gain,” Dr. Farooqi explained. “Between 40 and 70 percent of obesity can be attributed to genetic factors. That suggested genetic approaches might be used to discover the mechanisms of weight regulation.”
Dr. Farooqi has focused her clinical and research career on tracking down the genetic drivers and molecular signals that regulate weight. Her lab identified leptin as a major regulator of human appetite, pioneered leptin replacement therapy, and identified potential drug targets for safe and effective weight loss. She described this research journey in her award lecture, “Obesity and the Biology of Weight Regulation.”
Sparked by leptin findings in mouse models, Dr. Farooqi worked with obese patients to look for similar genetic anomalies. In 1997, her lab identified the first patients with congenital leptin deficiency. After just three days of leptin replacement, her first two patients refused food for the first time in their lives and began losing weight.
The leptin finding led to the Genetics of Obesity Study (GOOS), an ongoing cohort of more than 3,600 patients from around the world with different forms of genetic obesity. Study researchers discovered that leptin activity and appetite control are largely regulated by pathways that include the melanocortin 4 receptor (MC4R). More than 300 variants in the MC4R gene have been found, Dr. Farooqi said. Most decrease function, which increases appetite and weight.
The first MC4R agonist, setmelanotide, is in clinical trials to treat rare genetic disorders of obesity. But MC4R only accounts for 10 percent of the obesity in GOOS patients, Dr. Farooqi noted. There are more signaling cascades at work.
There’s also the flip side of obesity, thinness. Few researchers have looked at thin people, especially the thin and healthy, noted Dr. Farooqi, who worked with the National Health Service in the U.K. to launch the Study Into Lean and Thin Subjects. An initial GWAS survey found more than 100 loci associated with weight regulation.
Meanwhile, the U.K. BioBank has identified 61 MC4R variants. Most are loss of function, leading to obesity, but a few are gain of function, which protects against obesity and type 2 diabetes.
One MC4R variant, V102I, upregulates MC4R to signal loss of appetite, resulting in weight loss. Dr. Farooqi’s lab is investigating the variant as a drug target.
“Thin people are thin because they have less of the genetic variants that make people obese, not because they are morally superior,” said Dr Farooqi, tongue in cheek. “We are very interested in finding the genes that drive those phenotypes.”