How oestrogen could impact the MC4r gene in women and possible weight loss treatments

Recent life news, I’ve changed doctors practices and if you’re familiar with the process then you know you have a review with your new doctor. In preparation I’ve been looking more into MC4r deficiency so I can articulate myself well since most doctors don’t know what is. My hope is that a fresh start with my new doctor will help my mental state better although I will clarify this was not the reason for the change, my other practice announced a possible closure so it made sense to move.

Naturally I looked up recent MC4r news and found an article that peaked my interest. I’ve spoken about the IMCIVREE drug granted marketing authorization in the European Union for the treatment. However, there may be another treatment on the horizon.

Scientists have known for a century that female animals become more active just before they ovulate, which is an evolutionary trait to enhance their chances of mating while fertile. A team at UC San Francisco has identified specific neutrons and signalling pathways that make sexually repetitive females of many species (including humans) more active during this time.

When oestrogen baths in the brain it interacts with oestrogen receptor α (ERα) to activate the gene MC4r. This produces melanocortin-4 receptors on the surface of oestrogen-sensitive neurons in a part of the brain called the ventrolateral ventromedial hypothalamic nucleus (VMHvl) that regulates how energy is used in adult females.

The study team created a map of where proteins attach to DNA and identified two sites where ERα binds to MC4r to regulate its activity, establishing a clear link between the hormone receptor and the gene. The gene at the centre of the circuit, MC4r (the reason we’re here) is know for its role in regulating energy, appetite and weight and mutated forms of the genes can lead to obesity which can be particularly severe in females.

This research illuminates what happens to women during menopause as loss of oestrogen disrupts the energy circuit, meaning they become more sedentary, gain weight and develop metabolic disorders like type 2 diabetes.

The Importance of Oestrogen

The study above used female and male mice to come to their conclusion. Using a technique called DREADDs to make the VMHvl neurons express a receptor that could only be activated by a harmless chemical added to their water. Both sets of mice became more active, and the females lost nearly 10 per cent of their body weight after 24-hours of continuous administration. But, inhibiting these neurons had the opposite effect, making females more sedentary.

The same thing happened in female mice that lacked ovaries and had been put on a high-fat diet. A single instance of DREADD stimulation reversed the harmful metabolic effects of both oestrogen depletion and diet-induced obesity. Long-term administration caused obese mice to slim down dramatically, and it improved their overall metabolic health.

The reason these results are exciting is because they highlight the key role of MC4r and activity promoting neutrons suggesting how gene therapy tools might be adapted for genetic obesity treatments.

Doctors stopped prescribing hormone replacement therapy for symptoms of menopause in 2002 after a study found it increased the risk of endometrial and breast cancer, as well as blood clots and stroke. However, this new research suggests that hormone therapy can make a difference to a persons well-being and deserves another look.

Let’s at least find out what it’s doing, so maybe we can bypass it and get those positive effects of oestrogen another way, by another drug, another target. Until we have that, women are just stuck with, ‘You’re not going to have what makes you feel better.’ That’s why I’m so passionate about this research

Holly Ingraham, PhD, the Herzstein Professor of Molecular Physiology at UCSF

To me this is really exciting news. I like the idea that more research is being done on these topics and that possible treatments are starting to come out of the woodwork. I think it’s so important for people with genetic weight issues to have options available to them, to not live with (24/7 food) restrictions and to have doctors who understand the mental health implications that come with the burdens of a genetic obesity.

Yes, there are clearly things to work out, such as the research from the 2002 study. But this research is in it’s early days and still needs a lot of development. But for all of us other there with mutated genes, it’s hope.

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