�鶹Ƶ��

Obesity is often associated with high cholesterol, elevated triglycerides, and an increased risk of heart disease. But a new study, , published in Nature Medicine, suggests that not all obesity follows the same biological rules. Professor I. Sadaf Farooqi is a Professorial Fellow at �鶹Ƶ��, a Wellcome Principal Research Fellow and Professor of Metabolism and Medicine at the University of Cambridge, UK. An internationally leading Clinician Scientist, she has made seminal contributions to understanding the genetic and physiological mechanisms that underlie obesity and its complications.  Researchers on Sadaf’s team, investigating people with MC4R deficiency, have now discovered that, despite severe weight gain, these individuals tend to have lower levels of harmful blood lipids and a reduced risk of cardiovascular disease. The findings point to the brain as a surprising regulator of fat metabolism and heart health.

The brain-body connection in fat metabolism

The melanocortin 4 receptor (MC4R) is a protein found in the brain that helps regulate appetite and body weight. When functioning normally, MC4R balances food intake and energy expenditure through the leptin–melanocortin pathway, a system that links energy stores in fat tissue to brain activity. However, when MC4R is disrupted by genetic mutations, it leads to severe early-onset obesity caused by constant hunger and rapid weight gain in childhood.

Despite their obesity, people with loss-of-function MC4R mutations show something unexpected: their blood fat profiles are healthier than average. Researchers from the University of Cambridge, analysing data from over 7,700 participants in the Genetics of Obesity Study (GOOS) and more than 330,000 people from the UK Biobank, found that adults with MC4R deficiency had lower total cholesterol, LDL (“bad”) cholesterol, and triglycerides than weight-matched individuals without the mutation.

Obesity without the expected heart risk

Typically, obesity raises the risk of cardiovascular disease through dyslipidemia, an imbalance of blood fats that promotes artery-clogging plaque. However, this study found that MC4R-deficient individuals were partly protected from these metabolic risks, even when accounting for body fat. In both the GOOS and UK Biobank cohorts, MC4R mutation carriers had lower blood pressure and a reduced likelihood of hypertension or heart disease.

Interestingly, after eating a high-fat meal, participants with MC4R deficiency experienced a smaller rise in triglycerides and cleared them from the bloodstream faster than control participants. This means their bodies were better at storing fat in adipose tissue rather than allowing it to circulate in the blood, where it can contribute to plaque formation.

What’s happening inside the body?

The researchers believe that the brain’s regulation of the sympathetic nervous system (SNS) plays a key role. Normally, the MC4R pathway signals through the SNS to influence how the liver and fat tissue handle lipids. When MC4R function is lost, SNS activity drops, leading to changes in lipid metabolism, including potentially increased LDL receptor activity in the liver. This may enhance the clearance of cholesterol from the bloodstream, mimicking the effects of cholesterol-lowering drugs like PCSK9 inhibitors.

In essence, MC4R deficiency may push the body into a state that prioritises fat storage over fat circulation, reducing blood lipid levels and cardiovascular risk.

Implications for future therapies

These findings could shift how scientists think about obesity-related diseases. They highlight that not all obesity carries the same metabolic risks, and that the brain’s control of metabolism could offer new therapeutic targets. If researchers can understand how MC4R signaling lowers cholesterol without causing weight gain, it might be possible to develop treatments that protect against heart disease without altering appetite.

For university students studying biomedical sciences, genetics, or nutrition, this research is a powerful reminder that metabolism is not just about diet and exercise - it’s about the intricate dialogue between the brain, hormones, and body tissues. Understanding that connection may pave the way for the next generation of precision therapies for obesity and cardiovascular disease.

�鶹Ƶ�� Professor I. Sadaf Farooqi

Sadaf Farooqi is a Professorial Fellow at �鶹Ƶ��. She is a Wellcome Principal Research Fellow and Professor of Metabolism and Medicine at the University of Cambridge, UK. She is an internationally leading Clinician Scientist who has made seminal contributions to understanding the genetic and physiological mechanisms that underlie obesity and its complications. The work of Sadaf Farooqi and her colleagues has fundamentally altered the understanding of how body weight is regulated. With colleagues, she discovered and characterised the first genetic disorders that cause severe childhood obesity and established that the principal driver of obesity in these conditions was a failure of the control of appetite. Her work is often cited as an exemplar of how the translation of research into the mechanisms of disease can lead to patient benefit. She has received a number of awards including the 2024 Outstanding Clinical Investigator Award from the Endocrine Society. In 2021, she was elected as a Fellow of the Royal Society in recognition of her exceptional contribution to science.