The study shows Appetite control depends on signaling at the 'primary cilium,' mouse.  UC San Francisco researchers have discovered that Primary cilia are distinct from motile cilia, the finger-like projections that act as a sort of cellular conveyer belt, with functions such as removing debris from the lungs and windpipe. This study has published in Nature Genetics.

Immotile primary cilia were once thought to be vestigial, like a cellular appendix, but in the past decade, research at UCSF and elsewhere has revealed that these structures play a key role in many forms of hormonal signaling in the body. Neuroscientists are accustomed to thinking of brain signaling in terms of direct chemical or electrical communication among neurons at sites called synapses,

But the new findings reveal that chemical signaling at primary cilia may also play an important, and previously overlooked role. In addition, the findings suggest potential new therapeutic approaches to the growing global obesity epidemic.

Key signaling proteins in brain's hunger circuit meet in primary cilia

The modern epidemic of obesity is driven largely by environmental factors, including access to essentially unlimited sources of ready calories paired with increasingly sedentary lifestyles. But not everyone exposed to the same unhealthy conditions becomes overweight. Studies have estimated that genetics contribute between 40 and 70 percent to people's inclination towards unhealthy weight gain.

These imaging studies also examined a protein called adenylyl cyclase 3 (ADCY3), which, like MC4R, localizes to primary cilia and has been recently associated with obesity. This protein is known to mediate signaling through proteins like MC4R. The researchers conclude that ADCY3 and MC4R must come together in the primary cilia of PVN neurons.

To allow these cells to detect signals from the arcuate nucleus indicating high body-fat levels and to respond appropriately by reducing appetite. This suggests that if genetic mutations prevent MC4R from getting to the cilia, or if other genetic defects damage the primary cilium itself, the brain has no way to pull the emergency brake on weight gain.

Research highlights important role of cilia in neuronal signaling in the brain

The new study 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. The story also highlights an intriguing distinction between how the hypothalamus controls appetite on short versus long timescales.

The emerging picture, Vaisse says, is that fast signaling at synapses between hypothalamic neurons is responsible for making sure you only eat when you're hungry, while slower signaling sensed by the primary cilia of the same cells controls your body's long-term energy balance between calorie intake and expenditure.