While the prevalence of obesity increases each year and continues to underlie many serious health conditions in children and adults alike, the genetic aspects and pathophysiology associated with the disease are not fully understood. Consequently, the obscurity of the mechanisms underlying obesity makes treating affected patients difficult. Now more than ever, as we face an intercontinental obesity pandemic, our knowledge about the disease must grow faster than the climbing obesity rates.

Sources: NCHS, National Health Examination Survey and National Health and Nutrition Examination Surveys.

The Src homology 2 B adaptor protein 1 (SH2B1) has recently been identified as a gene associated with obesity, and SH2B1 mutations have been identified in a large cohort of patients with severe early-onset obesity. Three of the human mutations identified in the obese patients are located in the pleckstrin homology (PH) domain of SH2B1. The Carter-Su Lab is currently studying one of these point mutations (P322S) using a CRISP-Cas9 generated mouse model. Along with the P322S mouse model, the Carter-Su Lab has also generated a mouse model with a six base-pair deletion that causes a 2 amino acid deletion (ΔP317, R318) in the PH domain of SH2B1. This mouse model is important because it explores the function of the PH domain, which seems to be important for the function of SH2B1, yet has not been fully investigated. For my summer research project, I have been working on determining the metabolic phenotype of the ΔP317, R318 mice. I have been measuring the food intake and body weight of a cohort of 48 animals, as well as performing glucose tolerance tests and insulin tolerance tests to investigate whether the six base-pair deletion affects glucose metabolism. I am also performing blood draws to examine levels of insulin and leptin, the latter of which is referred to as the “satiety hormone.” My project using the ΔP317, R318 mouse model will help investigate the function of SH2B1 in regulating energy homeostasis as well as provide insight into the function of the PH domain of SH2B1, which is conserved across species. This is all extremely important since understanding how SH2B1 works will provide insight that may enable identification of new therapeutic targets for obesity.

Wild-type mouse (left) pictured next to a SH2B1β ΔP317,R318/ΔP317,R318 mouse (right).

Doing research in a lab is an incredibly rewarding experience. I have made plenty of mistakes along the way (my lab can verify this), but each day I am getting better. What surprised me the most about working in a research lab this summer was how much other people were truly willing to teach me — not because I asked them to or because they had to, but because they knew I wanted to learn. In research there is no “one size fits all” policy, and that is okay. It is all about finding what works for you. The reality is that the process of doing research is not perfect; things will go wrong, and that is a fact. The honest truth is that many experiments will have to be done…and redone, but in my case, all of the experiments I have performed in my 7 weeks so far have been successful in the end. My preliminary results are mostly what my research host and I expected, some of the phenotypes being even more extreme that originally hypothesized (cue obese mouse below!)

SH2B1β ΔP317,R318/ΔP317,R318 female on a scale weighing more than three times the amount of a wild-type female of comparable age.

There are days when I feel extremely frustrated, days when I think I’ll be stuck in lab all night, and days when I feel like the luckiest person in the world just to be where I am, doing what I’m doing. The day-to-day life of a scientist is different every day, and that is what draws many of us to science in the first place. Science allows us to be innovative and creative and to spend each day with other people who share similar interests, working on different pieces of our own puzzle. Working as part of a lab team has provided me with an amazing support system, and I could not be more thankful for that. As a member of a team, you are responsible for pulling your own weight, which is both a blessing and a curse. When something goes right, that is on you, but if something goes wrong, you must take responsibility for that too. The biggest struggle that comes with this is managing your time effectively, especially when faced with so many time sensitive issues. Your animals will not stop aging; your cells will not live forever if they are not split. The life of a scientist is a roller coaster, but it is one that I would choose to ride each day.

References

1. Overweight & Obesity Statistics | NIDDK. [online] National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/health-statistics/overweight-obesity [13 Jul. 2017].

Lauren DeSantis is a junior double majoring in Neuroscience and Spanish at the University of Michigan in Ann Arbor, MI. She is a 2017 Undergraduate Summer Research Fellow (UGSRF) doing research in Dr. Carter-Su’s lab in the Molecular and Integrative Physiology Department at the University of Michigan Medical School in Ann Arbor, MI. Lauren’s fellowship is funded by the APS. After graduation, she plans on pursuing her MD-PhD to become a neurosurgeon-neuroscientist.