The key to controlling hunger and fighting obesity is in brain cells that produce hormones, according to research.
A new study sheds light on the complex messaging system between neurons in the ‘hunger circuit’ and the brain.
Scientists showed that antenna-like structures on brain cells, called primary cilia, control appetite, which offers potential new options to treat obesity now that researchers know exactly which neurons to target.
Uncovering the neurological causes of obesity may combat one of the biggest health problems in the world that affects more than a third of adults in the US.
Previous research has revealed that most of the gene mutations that increase the risk of obesity are located in the brain.
Now it seems controlling appetite could all boil down to the primary cilia – microscopic sensory antennae neurons use to gather information about their environment.
Professor Christian Vaisse, of the University of California at San Francisco, said: ‘We’re building a unified understanding of the human genetics of obesity.
‘Until recently many obesity researchers had barely heard of primary cilia – but that’s going to change.’
Although obesity is driven by environmental factors, such as limitless access to sugar and fat-laden foods and increasingly sedentary lifestyles, not everyone becomes overweight.
It has been estimated genetics contribute up to 70 percent towards a person’s vulnerability to piling on the pounds.
Most mutations occur in the hypothalamus – the brain’s ‘hunger circuit’ that monitors levels of the hormone leptin that is secreted by fat cells and controls appetite.
Studies on humans and mice found mutations in genes linked to the chemical can’t detect when their body has already got plenty of fat – and constantly eat as if they were starving.
Now Dr Vaisse and colleagues have discovered how mutations in the gene MC4R – located in part of the hypothalamus called the arcuate nucleus – and cilia defects drive obesity.
By fluorescently tagging the MC4R protein in the brains of laboratory mice they found it was uniquely concentrated in the cells’ primary cilia – suggesting appetite-regulation occurs there.
The findings published in the journal Nature Genetics show that when mice expressed the mutated versions of the human MC4R gene seen in patients with extreme obesity it failed to reach the cilia.
When the researchers also blocked a protein called ADCY3 which – like MC4 – is found in primary cilia and has been associated with obesity – the animals significantly increased their food consumption and put on weight.
The researchers say ADCY3 and MC4R come together in the primary cilia of neurons in an area called the PVN (paraventricular nucleus).
This allows these cells to detect signals from the arcuate nucleus indicating high body-fat levels – and to reduce appetite.
But if mutations prevent MC4R from getting to the cilia – or other genetic defects damage the primary cilium itself – the brain has no way to pull the emergency brake on weight gain.
High leptin levels indicate excess body fat while low ones warn energy reserves are depleted.
The PVN neurons then send out instructions to the rest of the brain to adjust your appetite and energy level appropriately.
Dr Vaisse said: ‘It’s exciting how much progress this field has made.
‘In the ’90s we were asking whether or not obesity is genetic; a decade ago we were discovering that most obesity risk factors primarily impact the leptin circuit in the brain; and now we are on the verge of understanding how defects in this specific subcellular structure of a particular subset of hypothalamic neurons drives weight gain and obesity.’
He said it raises the possibility of developing treatments that could improve appetite control in people with obesity by modifying signaling at the primary cilia of MC4R-expressing neurons.
However, the development of treatments may still be a long way off.
Dr Vaisse said: ‘We still know so little about the primary cilium – and particularly how it is involved in signalling within these particular neurons.
‘We yet don’t know what we might do to fix it when it is broken.’