There is a pressing need for new therapeutic strategies for addressing the epidemic of obesity and its co-morbidities. Therefore, our lab aims to understand the molecular underpinnings of metabolic and cardiovascular disease and to identify new therapeutic targets for these highly prevalent diseases. We have developed and use a combination of mouse modeling, molecular biology, biochemical and genomic approaches to achieve this goal. One of our primary discovery platforms is mouse models of bariatric surgery. Bariatric surgery is defined as a surgical manipulation of the gut that is performed with the goal of body weight loss. However, bariatric surgery also produces cardiovascular and metabolic benefits that are independent of weight loss. Compelling work from our lab using mouse models of bariatric surgery has identified several new and exciting pathways that may prove useful in treating cardiometabolic disease. Specifically, our work in mouse bariatric models has led us to identify a new pathway regulating pancreatic islet function and a new pathway regulating bile acid metabolism that form two of the primary areas of research in our laboratory. These lines of research are described in further detail below:
Pancreatic islets are clusters of hormone-producing cells that orchestrate blood glucose regulation. Insulin is produced by islet beta cells and functions to decrease blood glucose. Glucagon is produced by islet alpha cells and functions to directly counter insulin action and increase blood glucose (Figure 1). While type 2 diabetes is classically thought to be due to a deficiency in insulin action, insulin-based therapeutics fail to cure this disease. Instead, we and others propose that glucagon excess is a key driver of type 2 diabetes, making it a compelling target for treatment. Using our mouse bariatric model, we have discovered a way to turn off production of the pro-diabetic hormone, glucagon, while simultaneously turning on an anti-diabetic hormone, glucagon-like peptide-1 (GLP-1), providing a potential therapeutic target that will bypass issues previously encountered with targeting glucagon action. Current studies are focused on using in vivo and in vitro techniques alongside untargeted proteomics, metabolomics and transcriptomics to define the physiology and biochemical mediators of this new pathway.
2. Bile Acid Metabolism
Bile acids are key regulators of metabolic homeostasis, and thus attractive therapeutic targets. Bile acids are synthesized in the liver and then metabolized by the gut microbiome (Figure 2). Our ongoing work seeks to define bile acid metabolic regulation in both of these compartments to enable targeting bile acids for the treatment of type 2 diabetes and cardiovascular disease.
Hepatic bile acid metabolism: We identified the bile acid receptor, TGR5, as a contributor to the glucoregulatory benefits of bariatric surgery. These studies used our mouse bariatric model to reveal a role for TGR5 in regulating gene expression to improve hepatic bile acid metabolism. Ongoing work aims to define the transcriptional and post-transcriptional regulation of the expression of genes involved in hepatic bile acid metabolism by TGR5.
Gut microbial bile acid metabolism: In parallel, we are performing studies investigating the mechanisms driving the metabolic benefits of dietary fiber supplementation. Dietary resistant starch supplementation mimics many of the benefits of bariatric surgery which has prompted us to investigate the mechanisms by which dietary resistant starch supplementation improves glucose regulation as a complementary approach to our mouse bariatric modeling work. In particular, we are using dietary resistant starch supplementation as a model with which to understand gut microbial bile acid metabolism.
06/20 – Cummings lab participated in #ShutDownSTEM: https://www.shutdownstem.com/. As members of the academic STEM community we are deeply saddened by the underrepresentation and violence toward people of color and pledge to continue to foster diversity and inclusion efforts within academic STEM. We plan to do so in the following ways:
- Continued education and engagement on issues of diversity and inclusion: We will regularly discuss articles addressing the issues of racial disparities within academic STEM. Examples of resources that we have found useful thus far include the following:
- Anti-Racist Resource Guide
- Academics for Black Survival and Wellness
- The Smithsonian National Museum of African American History and Culture
- The Smithsonian resources on Talking About Race.
- Science Has a Racism Problem: https://www.cell.com/cell/pdf/S0092-8674(20)30740-6.pdf
- Promotion of diversity and inclusion in our field of research:
- We will advocate for increased visibility of underrepresented minorities.
- We will regularly review articles on topics of relevance to our research from labs lead by underrepresented minorities and work to highlight these important contributions in our own work.
- Promotion of diversity and inclusion within Cornell and the broader Ithaca area. We plan to increase our engagement in outreach activities aimed at improving diversity in STEM such as:
We recognize that this is only the beginning and we look forward to continuing this dialog and improving and expanding upon our efforts.
Signed: Margot Chirikjian, Bethany Cummings, Samantha Fountain, Viraj Govani, Marlena Holter, Isaac Lee, Daryl Phuong, Mridu Saikia, Jenna Todero, Lisa Weikert, Journey Wise, Jared Zion
06/20 – Mridu Saikia presented on the effects of liraglutide in human islets at the virtual American Diabetes Association Scientific Sessions.
06/20 – Cummings lab featured by the Office of the Vice Provost for Research: https://research.cornell.edu/news-features/finding-new-targets-diabetes-treatment
05/20 – Margot Chirikjian successfully presented her senior honors thesis on the role of hepatocyte TGR5 in glucose regulation. Congratulations Margot!
04/20 – Marlena Holter awarded an NIH F30. Congratulations Marlena!
04/20 – Marlena Holter awarded an Alpco Diabetes Research Travel grant, Congratulations Marlena! https://www.alpco.com/company/diabetes-grant
03/20 – Margot Chirikjian accepted into graduate school with the Columbia University Nutritional and Metabolic Biology PhD program. Congratulations Margot!
12/19 – Holter et al. paper on hepatocyte p53 and bariatric surgery published in FASEB: https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fj.201902214R
09/19 – Mridu Saikia presented on the effects of liraglutide in human islets at the Weill-Ithaca Cornell Precision Nutrition Symposium and the Sugar Club meeting.
06/19 – Marlena Holter presented on the impact of bariatric surgery in mice with hepatocyte ablation of p53 at the annual American Diabetes Association Scientific Sessions.
05/19 – Mridu Saikia presented on the application of DART-seq to the study of human islets at the Boston-Ithaca Islet Club meeting and won the second place prize for best oral presentation, Good work!
05/19 – Eumee Cha successfully presented her senior honors thesis on the role of TGR5 in the effects of bariatric surgery on blood pressure regulation, Congratulations Eumee!
05/19 – Garibay et al. paper on the impact of bariatric surgery on colitis in mice published in Obesity Surgery: https://link.springer.com/article/10.1007/s11695-019-03707-9
04/19 – The Cummings lab received the Hartwell Foundation Individual Biomedical Research Award: https://news.cornell.edu/stories/2019/04/two-cornell-faculty-receive-hartwell-awards-biomedical-research
01/19 – The Cummings lab received the Schwartz Research Fund for Women in the Life Sciences award: https://www.vet.cornell.edu/news/20190125/dr-bethany-cummings-awarded-2019-schwartz-award
09/18 – Zaborska et al. review paper on bile acids and their role in metabolic disease published in Current Diabetes Reports: https://link.springer.com/article/10.1007%2Fs11892-018-1092-3
08/18 – Kieran Koch-Laskowski presented on the role of hypothalamic GLP-1R signaling on energy balance at the National Veterinary Scientists Symposium.
07/18 – Zaborska et al. paper on deoxycholic acid and glucose regulation published in PLoS One: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200908
06/19 – Michelle Reichert presented on the effects of dietary fiber on gut microbial bile acids to the Cornell Leadership Program and won the Molecular Biology Prize from the Leadership Program. Congratulations Michelle!
05/19 – Jon Lou wins the Hugh Dukes Prize in Experimental Physiology, Congratulations Jon!
04/19 – Jon Lou’s research experiences highlighted by the Office of the Vice Provost for Research: https://research.cornell.edu/news-features/innovative-vet-school-experience
12/18 – Marlena Holter received a Cornell Vertebrate Genomics scholarship in support of her work on islet GLP-1 receptor signaling. Congratulations Marlena!
06/18 – The Cummings lab received an award from the Department of Defense to expand on their beta cell GLP-1 receptor signaling work.
04/18 – Garibay et al. paper on the role of beta cell GLP-1R signaling on alpha cell GLP-1 production after bariatric surgery published in Cell Reports: http://news.cornell.edu/stories/2018/04/bariatric-surgery-successes-lead-type-2-diabetes-treatments
09/17 – Darline Garibay presented on the role of beta cell GLP-1R signaling in the metabolic benefits of bariatric surgery in mice at the BBS Symposium and won best poster!
06/17 – Darline Garibay presented on the role of beta cell GLP-1R signaling on the effects of bariatric surgery on islet morphology at the annual American Diabetes Association Scientific Sessions.
03/17 – Darline Garibay presented on the impact of beta cell GLP-1R signaling on alpha cell GLP-1 production after bariatric surgery in mice at the Mount Sinai Hospital Lunenfeld-Tanenbaum International Symposium: 30 Years of GLP-1 Biology.
12/17 – Garibay et al. paper on how to perform vertical sleeve gastrectomy on mice published in JOVE: https://www.jove.com/video/56534/a-murine-model-of-vertical-sleeve-gastrectomy
08/17 – Jon Lou presented on the role of beta cell GLP-1R signaling in alpha cell proglucagon processing in mice at the National Veterinary Scholars Symposium.
07/17 – Karolina Zaborska presented on the role of TGR5 in the effects of bariatric surgery on blood pressure in mice at the Keystone Symposium on Bile Acid Receptors as Signal Integrators in Liver and Metabolism.
03/17 – McGavigan et al. paper on the effect of bariatric surgery on blood pressure in mice published in Disease Models and Mechanisms: https://dmm.biologists.org/content/10/3/235.long
09/16 – Garibay et al. paper on the role of the beta cell GLP-1R in the metabolic benefits of bariatric surgery published in Endocrinology: https://academic.oup.com/endo/article/157/9/3405/2422376
08/16 – Jon Lou presented on the role of beta cell GLP-1R signaling in the effects of bariatric surgery on islet morphology at the Merial Veterinary Scholars Symposium.
06/16 – Darline Garibay presented on the role of beta cell GLP-1R signaling in the metabolic benefits of bariatric surgery in mice at the annual American Diabetes Association conference.
04/16 – The Cummings lab received an NIH/NCI R21 to study the impact of bariatric surgery on colorectal cancer development in mice.
10/15 – McGavigan et al. paper on the role of the bile acid receptor, TGR5, in the metabolic benefits of bariatric surgery published in Gut: http://www.news.cornell.edu/stories/2016/01/study-unravels-link-between-surgery-diabetes-remission
12/15 – Anne McGavigan received a Cornell Vertebrate Genomics Scholar award to support her work on the impact of bariatric surgery on blood pressure regulation in mice, Congratulations Anne!
07/15 – Anne McGavigan presented on the impact of bariatric surgery on blood pressure regulation in mice at the American Heart Association Hypertension Scientific Sessions with an abstract ranked in the top 10% of all abstracts in the meeting!
08/14 – The Cummings lab received a Lilly Research Award Program grant to study the role of TGR5 in the metabolic benefits of bariatric surgery in mice.
07/14 – The Cummings lab received a research award from the President’s Council of Cornell Women to develop a mouse model of Roux en Y Gastric Bypass.
04/14 – The Cummings lab received an award from the Comparative Cancer Biology Training Program to study the impact of bariatric surgery on hepatic cancer in mice.