Obesity has increasingly become a focus of pharmaceutical development as the disease itself affects quality of life for millions of people globally and causes an increase in risk of secondary conditions such as diabetes and MASH (metabolic dysfunction-associated steatohepatitis). An increasing number of mechanisms of action that result in weight loss have been identified resulting new anti-obesity targets and the opportunity for combinatorial therapies. To better understand the mechanisms of action of these different anti-obesity therapeutics, Gubra utilizes light sheet microscopy to image whole brains as therapies are preclinically developed.
Regulation of Energy Use in the Body
Regulation of hunger and satiation are essential for organismal survival and thus is a highly regulated process. There are several centers within the human brain focusing on metabolomics and energy expenditure to ensure that “hunger signals” from the digestive system are received, the process for feeding is initiated, “satiety signals” are received, feeding stops, and that energy from food is distributed throughout the body. If any part of this highly complex system of endocrine and neural signalling is disrupted, whether genetically as in the case of Prader-Willi Syndrome or hormonally in the case of misregulation of signalling due to neurodegenerative diseases, this can cause a feedback loop resulting in obesity as the organism cannot determine if it has enough energy to survive or has consumed enough food to replace any lost energy.
Anti-Obesity Therapy Induced c-Fos Activity
To best visualize the neural activity induced by therapies, Gubra utilizes whole brain c-Fos imaging. c-Fos is an immediate-early gene that is an indicator of neural activity and is produced in response to drugs that stimulate neural activity. If you want to learn more about c-Fos and its use in whole organ imaging, see our article here: Understanding c-Fos and its applications in CNS research.
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When anti-obesity drugs are introduced to an animal, in the short term, activation is observed in several regions of the brain. For example, most of the anti-obesity drug classes examined in “Whole-brain activation signatures of weight lowering drugs” activated components of the dorsal vagal complex (DVC). Knowing this, a hypothesis can be made that these compounds, by stimulating the DVC are resulting in strong satiation signals. These signals cause the animal to stop eating sooner than they would have without the therapy. Such insights during development of an obesity therapy allows for confirmation of target neuron activation, identification of any off-target activation, and better understanding of how the therapy compares to those on the market.
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Utilize whole brain imaging to measure c-Fos expression for your obesity therapy
Neural activation determined via c-Fos signal is a superior tool to provide significant insights into brain activity after exposure to pharmaceuticals. Leverage Gubra’s expertise in both obesity and 3D imaging to create a study to characterize your preclinical obesity therapy. Please contact us with your study ideas and for more information.
