Researchers studying obesity have discovered that antenna-like structures on brain cells that form part of the body's hunger circuit seem to play a key role in appetite regulation.

The study paper, published in the journal Nature Genetics, highlighted the important role that the antenna-like structures—or primary cilia—can play in brain signaling.

It was generally thought that most of the signaling in the brain occurred through structures called synapses.

"We're building a unified understanding of the human genetics of obesity," explains senior author Christian Vaisse, a professor in the Diabetes Center at the University of California, San Francisco.

"Until recently," he adds, "many obesity researchers had barely heard of primary cilia, but that's going to change."

The role of genetics in obesity

In the United States, obesity affects more than a third of (or 78.6 million) adults.

Obesity is a huge public health concern, not least because it is associated with poor mental health and many other serious medical problems. These include some of the leading causes of death in the US and the rest of the world, such as diabetes, stroke, heart disease, and some cancers.

The main drivers of the obesity epidemic are largely non-genetic, such as the combination of ready access to an unlimited supply of calorie-rich food and "increasingly sedentary lifestyles."

However, not everyone exposed to these environmental conditions becomes obese, suggesting that genetics also play a role.

In most diseases in which genetics play a role, the cause is due to variations in a number of genes. But sometimes, the cause can be due to variations in a single gene.

Hunger circuit

In their paper, the researchers explain that most single-gene causes of severe obesity are due to gene alterations in a hunger circuit that involves leptin—a signaling protein, or hormone, that is released by fat cells.

The circuit is a network of nerve cells, or neurons, in the hypothalamus area of the brain that helps to keep weight stable by adjusting appetite and energy usage depending on leptin levels.

Mutations in the gene that codes for leptin, or in genes involved in monitoring and responding to the protein, can lead to failure to detect when the body has a sufficient amount of fat. This can happen in mice and humans, causing them to keep eating "as if they are starving."

In previous work, Prof. Vaisse and colleagues found that mutations in a gene involved in the leptin hunger circuit—the melanocortin-4 receptor (MC4R) gene—account for 3%–5% of all cases of severe obesity in humans. Severe obesity is defined as having a body mass index (BMI) that is above 40.

The MC4R protein detects chemical signals in a special group of neurons in the hypothalamus that are thought to play an important role in reducing appetite in response to high levels of leptin.

Until the new study, scientists did not know how this subset of hypothalamic neurons regulates appetite control.

Primary cilia linked to obesity

Other members of the study team had also previously discovered that rare variations in genes that affect primary cilia can give rise to diseases that are nearly always accompanied by severe obesity, such as Alström and Bardet-Biedl syndromes. However, it was not clear how the cilia are linked to obesity.

In the new study, the researchers studied appetite-regulating hypothalamic neurons in normal mice and found that the MC4R protein concentrates in their primary cilia.

They also found that mice engineered to have the version of the gene that is linked to severe obesity in humans did not have the MC4R protein in those cilia.

These findings made the team wonder whether these primary cilia on the hypothalamic neurons were the main location for the appetite-regulating function of the leptin hunger circuit.

Recent discoveries have revealed that another protein called adenylyl cyclase 3 (ADCY3) is also linked to obesity, and that it also concentrates in primary cilia. ADCY3 is known to link up with MC4R when it sends signals.

Key locations of appetite-regulating signals

In a further set of experiments, the researchers found that after blocking ADCY3 in the mice, the animals increased their food intake significantly and started to become obese.

The researchers concluded that ADCY3 and MC4R work together in the primary cilia of the leptin-detecting neurons to help them detect that body fat levels are increasing, which, in turn, reduces appetite.

Genetic, or other, interference with these vital components could therefore result in the body not being able to apply the "emergency brake" on appetite control.

However, the researchers point out that there is still a lot to learn about the role of primary cilia in appetite regulation, and it is likely to be quite some time before new treatments based on this knowledge become available.

"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," says Prof. Vaisse.

""[A]nd 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."

Prof. Christian Vaisse