Prohormone dysfunction linked with overeating and obesity

A small group of nerve cells deep inside the brain plays a key role in how hungry we feel, how much we eat, and how much weight we gain. This group produces a “grandfather” form of hormones responsible for regulating these functions.

Now, a discovery by a team at the University of Michigan Medical School, Ann Arbor, MI, sheds new light on how that grandfather molecule is produced, and what can go wrong and raise the risk of overeating and obesity.

The findings were published online in the Journal of Clinical Investigation, and they could lead to new approaches to treating some forms of obesity, especially those with genetic roots. The study also improves the understanding of how the body controls the levels of hormones related to appetite and certain endocrine disorders.

The grandfather hormone, or prohormone, is called pro-opiomelanocortin (POMC). After it is produced by cells in the hypothalamus, it is chopped up to make several important appetite-regulating hormones.

This new study shows that before POMC can leave the cells that produce it, every copy has to pass a kind of inspection. This ensures that poorly made POMC copies are cleared in a timely manner. The process is called endoplasmic reticulum-associated protein degradation (ERAD).

The researchers showed that the ERAD process in POMC neurons controls food intake and obesity by tightly regulating the amount of POMC released by the cells. If ERAD fails, their experiments found, most POMC molecules get clumped and held inside the cell. That means far fewer appetite-regulating hormone molecules reach the rest of the body.

These experiments showed that mice with a broken ERAD system in their POMC neurons ate far more than usual and gained weight rapidly. The mice became obese, although they were fed a low-energy diet.

“Our findings demonstrate that, surprisingly but unequivocally, the ERAD machinery plays a key role in normal physiology,” said Ling Qi, PhD, a professor in the U-M Department of Molecular & Integrative Physiology, who led the team. “These new revelations identify new elements in disease pathogenesis, and will help us design novel therapeutic approaches and targets for preventing and treating obesity.”

ERAD in human obesity

A rare, severe form of childhood obesity arises from a mutation in the POMC gene, so the researchers explored the relationship between ERAD and this mutation.

Humans with the mutation, called C28F, feel constant hunger and have complete lack of control over eating. They become severely obese in their early years.

The researchers found that mutated POMC molecules evade the ERAD quality-control process and build up inside the brain cells where they were made, interfering with the production of normal POMC. In both mice with broken ERAD and patients with mutated POMC, the underlying reasons are the same: the built-up, misfolded POMC molecules clump together and keep the entire hormone factory from running smoothly.

Strangely, the buildup didn’t cause the cells to die. They just didn’t produce the POMC prohormone.

The researchers, including lead author Geun Hyang Kim, PhD, a postdoctoral fellow in the Qi lab, concluded that properly functioning ERAD provides a “safe space” for the cell to put finishing touches on its products, keeping the bad proteins from clumping together with the good ones.

This discovery opens the door to new experiments with drugs that could boost the ERAD process in POMC-producing brain cells.

To explore ERAD’s role in other prohormones, the researchers focused on POMC-producing cells in the arcuate nucleus of the hypothalamus, and a pair of ERAD quality-control molecules called Sel1L-Hrd1.

Previously, Dr. Qi and his colleagues demonstrated that problems with ERAD affect production of another prohormone, proAVP, which is the grandfather of a hormone called vasopressin that regulates water balance in the body. Mice lacking ERAD in vasopressin-producing neurons develop diabetes insipidus, just as humans with the same condition do.

“Whenever you generate mice exhibiting human disease-like phenotypes, you know you are working on something with fundamental importance,” Dr. Qi said. “The ultimate question for us is, can we manipulate this system to treat human diseases.”

For instance, he said, using the knowledge gained from these studies, a small-molecule drug might be developed to boost the activity of the ERAD machinery, to ensure that prohormones are handled correctly. The team is working with other U-M colleagues to test some of these ideas.

The research was funded by the National Institutes of Health and the American Diabetes Association. The work is part of the U-M Protein Folding Disease Initiative.

To read more about this study, click here.