Beyond Leptin and Ghrelin: Targeting Multiple Factors When Treating Obesity

ONE Lab

Although scientific research on obesity has typically focused on targeting hunger-related hormones, scientists are now looking to develop pharmaceutical therapies with multiple drug targets.

Obesity is one of the most prevalent chronic health conditions in the United States, affecting over one-third of adults and putting patients at risk for major health problems, including cardiovascular disease and type II diabetes.1 Therefore, it’s no surprise that obesity has been a hot topic in life science research community for the last few decades. However, despite attempts to identify pharmaceutical drugs to treat obesity, no truly effective treatments have been developed.

The modern era of obesity research kicked off in the 1990’s when the hormones leptin and ghrelin were first discovered. Leptin is a hormone that is secreted by fat cells and that acts on the brain to suppress hunger, thereby preventing weight gain. It is a long-acting effector molecule, so it acts over days and weeks as fat cells appear and disappear depending on food intake. In contrast, ghrelin (also known as the “hunger hormone”) is a fast-acting hormone that is secreted by the stomach. Levels of ghrelin spike before mealtimes, and it travels through the bloodstream to the hypothalamus in the brain, where it initiates the release of hunger-related neurotransmitters.2

Naturally, scientists initially assumed that targeting leptin or ghrelin could be the key to combating obesity, but their efforts failed to produce results. Even drugs that were shown to effectively block the activity of ghrelin could not prevent obesity. Hope was renewed in 2013 and 2014, with the discovery of hunger-related neuronal signaling molecules that could be targeted, but again, studies on the potential therapies were largely unsuccessful.3

Today, the general consensus within the field is that effective pharmaceutical treatments for obesity will need to target multiple factors related to obesity. For life science organizations that decide to take on the challenge of developing such therapies, collaborative research software can be a valuable tool for supporting collaboration and increasing research efficiency.

Exploring Possible Therapeutic Targets

Because targeting single factors has been unsuccessful for treating obesity, adopting a multi-faceted approach is the logical alternative. According to Dr. David E. Cummings of the University of Washington, who has been researching obesity since the discovery of ghrelin in the 1990’s, “In a redundant system, it’s hard to imagine that the removal of any one determinant is going to overpower the other.” Therefore, multiple factors need to be targeted. Here are some of the factors that are being considered as targets for future obesity therapies:

 

  • Protein sensors in the stomach. Scientists have discovered that there are proteins in the stomach that can sense when the stomach stretches to accommodate food. In addition, these protein sensors can detect changes in stomach pressure and volume.
  • Hormones released by intestinal endocrine cells. When food enters the intestine, endocrine cells release signaling molecules, including glucagon-like peptide (GLP-1), peptide YY, and oxyntomodulin, all of which have been identified as possible targets for possible obesity therapies.
  • Neurotransmitters. Studies show that multiple neurotransmitters, including dopamine, serotonin, and norepinephrine, affect feelings of hunger and satiety. They also regulate stress responses and reward-related pathways, which often play a role in unhealthy eating habits.
  • Neuropeptides. In addition to targeting neurotransmitters, some scientists are looking to target hunger-related peptides in brain cells. For instance, it was recently discovered that the pro-opiomelanocortin (POMC) protein decreases appetite.
  • Leptin. Through advances in brain imaging technology, scientists have realized that leptin acts in many areas of the cortex—not just the hypothalamus, as previously thought. However, evidence indicates that leptin works differently within different regions of the brain, so scientists are looking for therapies that target leptin, but only within specific sets of neurons.

 

 

 

In addition to finding an effective combinatorial targeting strategy, scientists must also consider possible side effects. So far, all of the attempts at developing obesity therapies with multiple targets have had caused adverse side effects. Since quality of life is a major reason why patients would choose a pharmaceutical treatment for obesity in the first place, it will be necessary to develop a product with minimal side effects in order to achieve commercial success.

Collaboration in the Obesity Drug Development Process

Successful development of an effective pharmaceutical treatment for obesity will require a significant amount of collaboration. Different research groups may search for obesity-related small molecules with different targets and then pool their findings to develop combinatorial formulations. Modern collaborative software can make it easier for researchers to share their data and to access each other’s results. In addition, since obesity research has now been going on for almost three decades in some labs, the software can significantly improve research efficiency by making it easier to find old data on hormones like leptin and ghrelin. Not only can they build on organizational knowledge, but they can also avoid unnecessary duplicate experiments.

BIOVIA ONE Lab is a collaborative software solution designed specifically for research in life science labs. If your organization is conducting research on complex conditions that require multifaceted targeting strategies, this technology can be an excellent tool for keeping all team members on the same page. Contact us today to learn more about our offerings!

  1. “Overweight and Obesity Statistics,” 2017, https://www.niddk.nih.gov/health-information/health-statistics/overweight-obesity
  2. “Hungering for Obesity Treatments,” March 21, 2017, http://cen.acs.org/articles/95/i13/Hungering-obesity-treatments.html
  3.  “The Search for Obesity Drugs Targets Hunger’s Complex Chemistry,” March 29, 2017, https://www.eurekalert.org/pub_releases/2017-03/acs-tsf032917.php