Obesity and depression: Doctors find genetic connection – Genetic defect causes obesity and postpartum depression

Two diseases, one cause: Changes in the so-called TRPC5 gene can cause obesity and depression in mothers after birth, as doctors have discovered. Both diseases are therefore caused by neurological disorders in the brain that are caused by this genetic defect. Gene therapy or drug treatments could provide relief in both cases in the future.

Both obesity and postpartum depression are a growing health problem worldwide. According to the World Health Organization, the number of obese adults has doubled since 1990, and among adolescents it has quadrupled. This has serious consequences for the metabolism and cardiovascular system of those affected, among other things.

Ten to 15 percent of mothers suffer from depression after giving birth. While fewer women die today as a result of infections or blood loss during childbirth, postpartum depression continues to pose a major risk of death for mothers in the months following birth.

Link between obesity and depression

Obesity and postpartum depression could have the same biological cause and possibly a genetic defect, as a new study now suggests. A team led by Yongxiang Li from Baylor College of Medicine identified two unrelated boys with similar behavior. Both suffered from intense eating addiction, severe obesity and altered social behavior. Genetic analyses showed that a small piece was missing from each of the boys’ X chromosomes. This section of the genome contained the so-called TRPC5 gene.

The mothers of these two boys also showed striking connections: “Their mothers suffered from obesity, anxiety and postpartum depression. We found that they were carriers – the TRPC5 gene was missing from one of their two X chromosomes,” says senior author Sadaf Farooqi from the University of Cambridge. The two children and their siblings had each inherited the X chromosome with the genetic defect.

What role does the TRPC5 gene play?

TRPC5 plays an important role in the brain: “Previous studies have shown that disrupting the TRPC5 gene in the brain in mice leads to increased food intake and lower energy expenditure, thus causing obesity,” says co-author Yong Xu of Baylor College of Medicine in Houston.

Li’s team then investigated the role of TRPC5 in nerve cells in the brain in obesity and postpartum depression. To do this, they inserted a defective TRPC5 gene into the genome of mice and analyzed the consequences this had for the animals.

TRPC5 gene regulates behavior in mice and humans

It was found that male mice with this genetic defect gained a lot of weight, just like the two boys. They were also more anxious, agitated and less social than animals without the defective TRPC5 gene, the team reports. Female mice with this genetic defect showed the same symptoms as male mice. In addition, they developed symptoms of depression after birth and cared less for their offspring. Female mice that did not have offspring, on the other hand, did not develop any symptoms of depression despite the genetic defect.

“These experiments show that the characteristics and behaviors observed in humans with a defective TRPC5 gene were also present in our mouse model,” says Xu. “The tests thus demonstrate that TRPC5 regulates various innate behaviors in mammals.”

Two nerve cells identified

To find out the mechanism by which this gene controls our behavior, the doctors conducted follow-up experiments on various cell cultures and mice, removing the TRPC5 gene or inserting mutations.

The experiments revealed that two specific types of nerve cells in our brain can be regulated by TRPC5. Both neurons are found in the hypothalamus, the team found. This brain region is responsible for instincts such as feeding, fear, socialization and maternal care, among others.

The so-called Pomc neurons are located in the arcuate nucleus of the hypothalamus and normally help regulate food intake and body weight via the hormones insulin and serotonin. However, when the TRCP5 gene in the Pomc nerve cells was damaged, the mice had a stronger appetite and ate excessively, as Li and his colleagues explain.

Genetic defect affects innate behavior

The second type of TRPC5-sensitive nerve cells is located in the paraventricular nucleus of the hypothalamus (PVH) and produces the bonding hormone oxytocin. These so-called oxytocin neurons normally help regulate the body’s energy balance, process stress and emotions, and support mother-child bonding, the doctors report.

“Removing the TRPC5 gene from PVH oxytocin neurons in mice resulted in severe overeating and obesity in both sexes, as well as postpartum depressive behavior and reduced maternal care in females,” reports Xu.

In further experiments, Li and his colleagues investigated what happens in the oxytocin neurons when the defective TRPC5 gene is repaired and becomes active again. The result: the mice’s behavior returned to normal. They lost weight and behaved less anxiously. “Taken together, the results show that these innate maternal behaviors are mediated by TRPC5 on oxytocin neurons,” says Xu.

New approach to diagnosis and therapy

The findings could now be used to develop new therapies or diagnostic procedures for obesity and postpartum depression. For example, genetic analyses could help with the diagnosis: “Our work supports screening for TRPC5 to make a clinical diagnosis for these diseases,” says Farooqi.

In addition, drugs that target the mechanism of the TRPC5 gene or the protein it encodes – the ion channel Trpc5 (Transient Receptor Potential Channel 5) – could alleviate the symptoms of those affected. For example, the Pomc neurons in the patient’s brain could be specifically activated by active substances in order to compensate for the reduced activation via Trpc5 in the case of genetic defects. Such drugs are already approved for the treatment of genetically caused obesity, as the doctors report.

In the future, active substances that bind to oxytocin receptors on nerve cells could also be used to treat postpartum depression. This could be the hormone oxytocin itself or a similar substance. Gene therapies that repair the defect in the TRPC5 gene are also conceivable.

Frequency unclear

It is still unclear how many people worldwide have a genetic defect in the TRPC5 gene. An initial analysis of the genetic material of around 450,000 people from Great Britain found that 369 people had a mutation in this gene. They were all overweight, as Li and his colleagues report.

“This research reminds us that many behaviors we assume are completely under our control have a strong basis in biology – be it our eating behavior, anxiety, or postnatal depression. We need to have more understanding and compassion for people who suffer from these conditions,” says Farooqi. (Cell, 2024; doi: 10.1016/j.cell.2024.06.001)

Source: Baylor College of Medicine, University of Cambridge

July 3, 2024 – Claudia Krapp