November 03, 2016
2 min read

Gene mutation linked with preference for high fat, less sugar in adults

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NEW ORLEANS —The melanocortin-4-receptor protein is key to modulating food preference in humans and can have a unique influence on adults with obesity, according to a speaker at ObesityWeek.

In adults with and without obesity with a melanocortin-4-receptor (MC4R) mutation, researchers have found an increased craving for high-fat foods, but a decreased craving for high-sucrose foods, Sadaf Farooqi, PhD, FRCP, FMedSci, professor at the University of Cambridge Metabolic Research Laboratories, said during a keynote presentation.

“Essentially what we have is the patients are driven to have an increased fat preference at the expense of sucrose preference,” Farooqi said. “Why would this occur? Remember, this pathway is there to defend against starvation. There is a physiological relevance for this pathway.”

Typically, pro-opiomelanocortin (POMC) neurons, which suppress food intake, and agouti-related peptide (AgRP) neurons, which increase food intake, act together on the MC4R receptor, Farooqi said. If that signal is blocked, a person will experience an increase in fat intake, characterized by increased fat preference and decreased sucrose preference.

“This would confer an evolutionary advantage,” Farooqi said. “If you’re starving, which is when this pathway kicks in, it makes sense to eat more fat. It gives you twice as many calories per gram as carb or protein. But why does it make sense to not eat sugar? You can’t store excess sugar if you’re starving, whereas you can with excess fat.”

The findings converge with data from animal models showing that the circuits that regulate appetite also influence the rewarding properties of food and food preference, Farooqi said.

The MC4R mutation also has another surprising benefit. Despite having even severe obesity, many adults with the mutation are protected from hypertension, Farooqi said.

In studies with diet-induced obese mice, the obese mice would develop hypertension, whereas the obese mice lacking leptin or a leptin receptor would not develop hypertension, despite a high-fat diet, Farooqi said.

“What this means is leptin is a key signal linking weight and blood pressure,” Farooqi said. “The pathway looks something like this: If you have more fat, you make more leptin. Leptin goes to the brain, acts in the hypothalamus on this melanocortin circuit, and if you have increased leptin with obesity, you get increased tone through this circuit.”

That increased tone, Farooqi said, ultimately increases sympathetic tone, driving up heart rate, blood pressure and the blood pressure response to stress.

“This pathway is a key reason why as people gain weight, their blood pressure goes up, and as they lose weight their blood pressure goes down,” Farooqi said. “That is a physiological response mediated by leptin and these circuits.” – by Regina Schaffer


Farooqi S. Neural and Physiological Mechanisms Involved in Human Energy Balance. Presented at: ObesityWeek 2016; Oct. 31-Nov. 4, 2016; New Orleans.

Disclosure: Farooqi reports no relevant financial disclosures.