Why the ‘thrifty gene’ hypothesis is back

{"text":[[{"start":null,"text":"

"}],[{"start":6.4,"text":"The writer is a science commentator"}],[{"start":9.48,"text":"The two-faced Roman god Janus was able to look in opposing directions at once. His likeness often featured on doorways, including Rome’s most famous portal, the Janus Geminus, which remained open while the city-state was at war and closed during peacetime. "}],[{"start":31.53,"text":"That duality came to mind with the publication last week of a study showing that a genetic mutation that causes obesity might paradoxically also protect against high cholesterol and heart disease. This counter-intuitive link potentially opens the door to future drugs that could target both. "}],[{"start":54.47,"text":"It could also partly resuscitate the unfashionable “thrifty gene” hypothesis, first floated in the 1960s: that fat-storing genes helped our ancestors to survive periods of scarcity but today lead to obesity, diabetes and heart disease. The discovery that obesity-causing mutations come with some health benefits encourages us to revisit the idea of genes as good or bad and instead regard our long evolutionary history as a winding trail of delicate genetic trade-offs. "}],[{"start":99.77,"text":"The study focused on MC4R, the gene most widely linked to obesity in childhood. It encodes for a brain protein that acts like a brake on hunger: when the gene works properly, we stop eating when we are full. But mutations in that gene — carried by about one in 300 people in the UK — can lower protein levels, disrupting satiety signals and prompting overeating. Carriers can have a mutation in either one or both copies of the gene — we inherit two copies of every gene, one from each biological parent — and are often severely obese by the age of 10. "}],[{"start":146.26999999999998,"text":"A team of researchers led by Sadaf Farooqi, professor of metabolism and medicine at Cambridge university in the UK, wanted to study this cohort more closely. Using their own database of obese patients with a variety of genetic disorders, the team identified 144 adults with MC4R deficiencies — and found something surprising. Despite severe obesity, they showed better markers of heart health, including blood pressure, than comparably obese people without the mutation. "}],[{"start":185.65999999999997,"text":"“Unexpectedly, even though they really struggle with their weight, they have remarkably normal levels of cholesterol, in particular LDL cholesterol and triglycerides,” Farooqi tells me. LDL refers to low-density lipoprotein cholesterol, often called “bad” cholesterol; triglycerides are fats that can harden arteries and thicken artery walls. Both are implicated in heart disease."}],[{"start":213.55999999999997,"text":"The scientists then turned to the UK Biobank, a separate health dataset on half a million people, to check whether the association held up. It did: people carrying at least one MC4R mutation also had more positive markers of heart health than those of similar body weight with a fully functioning gene, along with lower rates of high blood pressure and lower self-reported use of blood pressure medication. The study, published in Nature Medicine, also found that carriers and non-carriers given a high-fat meal — a calorific chocolate milkshake — metabolised it differently. "}],[{"start":253.39999999999998,"text":"The association between the MC4R mutation, affecting a brain protein, and metabolic health looks causal but, Farooqi admits, this is difficult to prove. Still, one plausible mechanism that can tie them together is the sympathetic nervous system, which is responsible for the fight-or-flight response and involved in burning calories.   "}],[{"start":280.15,"text":"The MC4R gene could now become a therapeutic target for reducing the risk of high cholesterol and cardiovascular disease, as statins do. The researchers are also exploring the genetic secrets of the slim, with a view to finding new weight-loss drugs (people who produce high levels of the protein linked to MC4R tend to be thin). Farooqi has consulted for a variety of drug companies, including Mounjaro maker Eli Lilly, but says the MC4R work was funded by her own group."}],[{"start":319.49,"text":"The finding, meanwhile, supports the thrifty gene hypothesis. One reason the theory fell out of favour is the implication, against observation, that obesity should be universal. But despite that, Farooqi says, the MC4R mutation would clearly have benefited our ancestors: “Not only does it make people more hungry, but they absorb fat more quickly out of circulation and store it more easily . . . You’d survive deprivation better if you had one of these faulty genes.” Interestingly, the compulsion to eat is particularly strong during childhood, the most precarious time for survival."}],[{"start":364.84000000000003,"text":"This research, then, offers another surprising duality: a portal to both the future, in terms of a potential treatment for heart disease, and perhaps to an improved understanding of our evolutionary past.  "}],[{"start":389.03000000000003,"text":""}]],"url":"https://audio.ftcn.net.cn/album/a_1762160224_8496.mp3"}