Genetic study points to oxytocin as possible treatment for obesity and postnatal depression
Obesity and postnatal depression are significant global health problems. Postnatal depression affects more than one in 10 women within a year of giving birth and is linked to an increased risk of suicide, which accounts for as many as one in five maternal deaths in high income countries. Meanwhile, obesity has more than doubled in adults since 1990 and quadrupled in adolescents, according to the World Health Organization.
While investigating two boys from different families with severe obesity, anxiety, autism, and behavioural problems triggered by sounds or smells, a team led by scientists at the University of Cambridge, UK, and Baylor College of Medicine, Houston, USA, discovered that the boys were missing a single gene, known as TRPC5, which sits on the X chromosome.
Further investigation revealed that both boys inherited the gene deletion from their mothers, who were missing the gene on one of their X chromosomes. The mothers also had obesity, but in addition had experienced postnatal depression.
To test if it was the TRPC5 gene that was causing the problems in the boys and their mothers, the researchers turned to animal models, genetically-engineering mice with a defective version of the gene (Trpc5 in mice).
Male mice with this defective gene displayed the same problems as the boys, including weight gain, anxiety, a dislike of social interactions, and aggressive behaviour. Female mice displayed the same behaviours, but when they became mothers, they also displayed depressive behaviour and impaired maternal care. Interestingly, male mice and female mice who were not mothers but carried the mutation did not show depression-like behaviour.
Dr Yong Xu, Associate Director for Basic Sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine, said: “What we saw in those mice was quite remarkable. They displayed very similar behaviours to those seen in people missing the TRPC5 gene, which in mothers included signs of depression and a difficulty caring for their babies. This shows us that this gene is causing these behaviours.”
TRPC5 is one of a family of genes that are involved in detecting sensory signals, such as heat, taste and touch. This particular gene acts on a pathway in the hypothalamus region of the brain, where it is known to control appetite.
When the researchers looked in more detail at this brain region, they discovered that TRPC5 acts on oxytocin neurons – nerve cells that produce the hormone oxytocin, often nicknamed the ‘love hormone’ because of its release in response to displays of affection, emotion and bonding.
Deleting the gene from these oxytocin neurons led to otherwise healthy mice showing similar signs of anxiety, overeating and impaired sociability, and, in the case of mothers, postnatal depression. Restoring the gene in these neurons reduced body weight and symptoms of anxiety and postnatal depression.
In addition to acting on oxytocin neurons, the team showed that TRPC5 also acts on so-called POMC neurons, which have been known for some time to play an important role in regulating weight. Children in whom the POMC gene is not working properly often have an insatiable appetite and gain weight from an early age.
Professor Sadaf Farooqi from the Institute of Metabolic Science at the University of Cambridge said: “There's a reason why people lacking TRPC5 develop all of these conditions. We’ve known for a long time that the hypothalamus plays a key role in regulating ‘instinctive behaviours’ – which enable humans and animals to survive – such as looking for food, social interaction, the flight or fight response, and caring for their infants. Our work shows that TRPC5 acts on oxytocin neurons in the hypothalamus to play a critical role in regulating our instincts.”
While deletions of the TRPC5 gene are rare, an analysis of DNA samples from around 500,000 individuals in UK Biobank revealed 369 people – around three-quarters of whom were women – that carried variants of the gene and had a higher-than-average body mass index.
The researchers say their findings suggests that restoring oxytocin could help treat people with missing or defective TRPC5 genes, and potentially mothers experiencing postnatal depression.
Professor Farooqi said: “While some genetic conditions such as TRPC5 deficiency are very rare, they teach us important lessons about how the body works. In this instance, we have made a breakthrough in understanding postnatal depression, a serious health problem about which very little is known despite many decades of research. And importantly, it may point to oxytocin as a possible treatment for some mothers with this condition.”
There is already evidence in animals that the oxytocin system is involved in both depression and in maternal care and there have been small trials into the use of oxytocin as a treatment. The team say their work provides direct proof of oxytocin’s role, which will be crucial in supporting bigger, multi-centre trials.
Professor Farooqi added: “This research reminds us that many behaviours which we assume are entirely under our control have a strong basis in biology, whether that’s our eating behaviour, anxiety or postnatal depression. We need to be more understanding and sympathetic towards people who suffer with these conditions.”
This work was supported by Wellcome, the National Institute for Health and Care Research (NIHR), NIHR Cambridge Biomedical Research Centre, Botnar Fondation and Bernard Wolfe Health Neuroscience Endowment.
Reference
Li, Y, Cacciottolo, TM & Yin, N. Loss of Transient Receptor Potential Channel 5 Causes Obesity and Postpartum Depression. Cell; 2 July 2024; DOI: 10.1016/j.cell.2024.06.001
Scientists have identified a gene which, when missing or impaired, can cause obesity, behavioural problems and, in mothers, postnatal depression. The discovery, reported today in Cell, may have wider implications for the treatment of postnatal depression, with a study in mice suggesting that oxytocin may alleviate symptoms.
This research reminds us that many behaviours which we assume are entirely under our control have a strong basis in biology. We need to be more understanding and sympathetic towards people who suffer with these conditionsSadaf FarooqiOlli Turho (Getty Images)Illustration of a tired African American mother crying
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Largest ever genetic study of age of puberty in girls shows links with weight gain
In the largest study of its kind to date, an international team led by researchers at the Medical Research Council (MRC) Epidemiology Unit, University of Cambridge, studied the DNA of around 800,000 women from Europe, North America, China, Japan, and Korea.
Published today in Nature Genetics, the researchers found more than 1,000 variants – small changes in DNA – that influence the age of first menstrual period. Around 600 of these variants were observed for the first time.
The age at which girls hit puberty and start having periods normally occurs between ages 10 to 15, though this has been getting earlier and earlier in recent decades. The reasons for this are not fully understood. Early puberty is linked with increased risk of a number of diseases in later life, including type 2 diabetes, cardiovascular disease, and certain cancers. Later puberty on the other hand, has been linked to improved health in adulthood and a longer lifespan.
Just under half (45%) of the discovered genetic variants affected puberty indirectly, by increasing weight gain in early childhood.
Corresponding author Professor John Perry said: “Many of the genes we’ve found influence early puberty by first accelerating weight gain in infants and young children. This can then lead to potentially serious health problems in later life, as having earlier puberty leads to higher rates of overweight and obesity in adulthood.”
Previous work by the team – together with researchers at Cambridge’s MRC Metabolic Diseases Unit – showed that a receptor in the brain, known as MC3R, detects the nutritional state of the body and regulates the timing of puberty and rate of growth in children, providing a mechanism by which this occurs. Other identified genes appeared to be acting in the brain to control the release of reproductive hormones.
The scientists also analysed rare genetic variants that are carried by very few people, but which can have large effects on puberty. For example, they found that one in 3,800 women carry variants in the gene ZNF483, which caused these women to experience puberty on average, 1.3 years later.
Dr Katherine Kentistou, lead study investigator, added: “This is the first time we’ve ever been able to analyse rare genetic variants at this scale. We have identified six genes which all profoundly affect the timing of puberty. While these genes were discovered in girls, they often have the same impact on the timing of puberty in boys. The new mechanisms we describe could form the basis of interventions for individuals at risk of early puberty and obesity.”
The researchers also generated a genetic score that predicted whether a girl was likely to hit puberty very early or very late. Girls with the highest 1% of this genetic score were 11 times more likely to have extremely delayed puberty – that is, after age 15 years. On the other hand, girls with the lowest 1% genetic score were 14 times more likely to have extremely early puberty – before age 10.
Senior author and paediatrician Professor Ken Ong said: “In the future, we may be able to use these genetic scores in the clinic to identify those girls whose puberty will come very early or very late. The NHS is already trialling whole genome sequencing at birth, and this would give us the genetic information we need to make this possible.
“Children who present in the NHS with very early puberty – at age seven or eight – are offered puberty blockers to delay it. But age of puberty is a continuum, and if they miss this threshold, there’s currently nothing we have to offer. We need other interventions, whether that’s oral medication or a behavioural approach, to help. This could be important for their health when they grow up.”
The research was supported by the Medical Research Council and included data from the UK Biobank.
Reference
Kentistou, KA & Kaisinger, LR, et al. Understanding the genetic complexity of puberty timing across the allele frequency spectrum. Nat Gen; 1 July 2024; DOI: 10.1038/s41588-024-01798-4
Genes can indirectly influence the age at which girls have their first period by accelerating weight gain in childhood, a known risk factor for early puberty, a Cambridge-led study has found. Other genes can directly affect age of puberty, some with profound effects.
Many of the genes we’ve found influence early puberty by first accelerating weight gain in infants and young children. This can then lead to potentially serious health problems in later lifeJohn PerryHalfpoint Images (Getty Images)Portrait of a young girl writing in her diary
The text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.
Exercising during pregnancy normalises eating behaviors in offspring from obese mice
Previous studies in both humans and animal models have shown that the offspring of mothers living with obesity have a higher risk of developing obesity and type 2 diabetes themselves when they grow up. While this relationship is likely to be the result of a complex relationship between genetics and environment, emerging evidence has implicated that maternal obesity in pregnancy can disrupt the baby’s hypothalamus—the region of the brain responsible for controlling food intake and energy regulation.
In animal models, offspring exposed to overnutrition during key periods of development eat more when they grow up, but little is known about the molecular mechanisms that lead to these changes in eating behavior.
In a study published today in PLOS Biology, researchers from the Institute of Metabolic Science and the MRC Metabolic Diseases Unit at the University of Cambridge found that mice born from obese mothers had higher levels of the microRNA miR-505-5p in their hypothalamus—from as early as the fetal stage into adulthood. The offspring of obese mothers chose to eat more specifically of foods that were high in fat, which is consistent with fat sensing being disrupted in the hypothalamus.
Dr Laura Dearden from the Institute of Metabolic Science, the study’s first author, said: “Our results show that obesity during pregnancy causes changes to the baby's brain that makes them eat more high fat food in adulthood and more likely to develop obesity.”
Senior author Professor Susan Ozanne from the MRC Metabolic Diseases Unit and Institute of Metabolic Science said: “Importantly, we showed that moderate exercise, without weight loss, during pregnancies complicated by obesity prevented the changes to the baby's brain.”
Cell culture experiments showed that miR-505-5p levels can be influenced by exposing hypothalamic neurons to long-chain fatty acids and insulin, which are both high in pregnancies complicated by obesity. The researchers identified miR-505-5p as a regulator of pathways involved in fatty acid uptake and metabolism – high levels of the miRNA make the offspring brain unable to sense when they are eating high fat foods. Several of the genes that miR-505-5p regulates are associated with high body mass index in human genetic studies, showing these same changes in humans can cause obesity.
The study is one of the first to demonstrate the molecular mechanisms linking nutritional exposure in utero to eating behavior.
Dr Dearden added: “While our work was only carried out in mice, it may help us understand why the children of mothers living with obesity are more likely to become obese themselves, with early life exposures, genetics and current environment all being contributing factors.”
Reference
Dearden, L et al. Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food. PLOS Biology; 4 Jun 2024; DOI: 10.1371/journal.pbio.3002641
Adapted from a press release by PLOS Biology
Maternal obesity in pregnancy changes the eating behaviors of offspring by increasing long-term levels of particular molecules known as microRNAs in the part of the brain that controls appetite – but this can be changed by exercise during pregnancy, a study in obese mice has suggested.
We showed that moderate exercise, without weight loss, during pregnancies complicated by obesity prevented the changes to the baby's brainSusan OzanneEngin_Akyurt (Pixabay)Fast food meal of burger and fries
The text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright ©University of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.