The Panacea for Obesity: Fat!

Hello fellow science lovers!  Since my last blog post[i], I have been quite busy and have generated exciting and perplexing data.  As a brief reminder, I am working within the Division of Endocrinology, Diabetes and Metabolism at Beth Israel Deaconess Medical Center and Harvard Medical School[ii], focusing on hydrogen sulfide signaling using genetic knockout mouse models.  In particular, I am focusing my research on a knockout (KO) mouse strain for the major hepatic (liver) endogenous hydrogen sulfide producing enzyme, cystathionine gamma lyase (CGL). When I wrote my last blog post, I was beginning to examine key gene expression and protein expression levels between wild type (WT) control mice and CGLKO mice by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR)[iii] and Western Blots[iv] respectively.  I continue to rely on these powerful molecular biology methods, where I attempt to connect the dots between differential gene and protein expression levels.  Recently, my data has lead me towards a nutritional framework, where I have been particularly interested in dietary-induced and dietary-resistant obesity.

Pictured on the right is the ob/ob mouse strain compared to a normal, wild type mouse strain on the left. Ob/ob mice are deficient in the feeding inhibiting hormone leptin, and thus are used in obesity and diabetes research [vii].
Given the pervasive rise in obesity and diabetes within the United States (US), therapeutic targets for dietary-resistance to obesity are a “hot” research topic within the field of Endocrinology and Metabolism.  In a special report published in 2005 within the New England Journal of Medicine (NEJM), the authors predict “that as a result of the substantial rise in the prevalence of obesity and its life-shortening complications such as diabetes, life expectancy at birth and at older ages could level off or even decline within the first half of this century.”[v] This stands in stark contrast to human trends, where human life expectancy has steadily increased over the past thousand years [v].  Thus, the need for breakthrough research discoveries regarding obesity, metabolic disease, and diabetes has never been more imperative.  A major research target in recent publications has been the heat-generating, master energy consuming mammalian brown fat, or brown adipose tissue (BAT) [vi].

In mammals, BAT is a major tissue site for chemical production of heat (thermogenesis) from fats, which has made BAT a promising target to induce weight loss[vi].  Traditionally, when exposed to cold temperatures, humans generate heat by shivering [vi].  However, mammals such as mice and human infants possess vast BAT depots, allowing thermogenesis during cold exposure to be driven by the chemical uncoupling of cellular energy production, oxidative phosphorylation [vi].  This chemical uncoupling of oxidative phosphorylation is achieved in part through expression of uncoupling protein-1 (Ucp1) [vi]. Additionally, white fat or white adipose tissue (WAT), the classic form of stomach fat we all attempt to minimize, can be induced into a BAT like state, known as “beige” or “brite” fat [vi].  This beige fat has thermogenic capacity, and because thermogenesis relies on the breakdown of fat depots in order to generate heat, beige fat has the ability to burn excess fat depots and promote a healthier metabolic system [vi].  Countless studies have demonstrated that “expanding the activity of brown fat, beige fat or both in mice through genetic manipulation, drugs or transplantation suppresses metabolic disease.”[vi] One such stimulus for expanding beiging of WAT is dietary control.  Thus, because of the vast therapeutic potential of beige fat and BAT, I have been particularly fascinated by diets that can induce beige fat and or increase BAT activity.  Such a diet could have broad reaching implications for metabolic disease, and could help reduce the estimated 300,000 deaths per year related to obesity [v].

Here, major anatomical depots of brown adipose tissue (BAT), white adipose tissue (WAT) and beige adipocytes are depicted. This figure portrays differences between fat locations in (a) mice and (b) humans.   Genetic markers are given for each adipocyte type in the lower right hand corner  [viii].
Compared to my classroom studies at Brandeis, working in a biomedical research lab allows me to explore complex physiological topics that I would never confront in an undergraduate class, such as BAT and beige fat thermogenesis.  After running experiments on RNA, DNA, and proteins extracted from both control (WT) and CGLKO mice, the results almost always spur me to read a slew of research papers and reviews, which guide me towards a holistic understanding of what is occurring inside my mice. For example, I have examined Ucp1 expression levels in my mice, leading me towards reviews regarding thermogenesis. This ability to read beyond only what is assigned to me is a wonderful aspect of research which is mostly absent as an undergraduate at Brandeis.  I find this freedom allows me to become more excited about the material, and often causes me to gleefully share theories of mine with my co-workers, most of whom are post-doctoral fellows.

Similar to last summer, I am loving the environment of working in a basic science research lab.  I am continually refining my molecular techniques, learning new assays weekly, such as the protein concentration quantification bicinchoninic acid (BCA) assay[ix].  With each data result or conversation with the post-doctoral fellow I work alongside, I learn new complex signaling pathways within mammalian physiology.  After each biweekly lab meeting, I learn new elements of modern thyroid research, continually building upon my knowledge base of intricate thyroid endocrine regulation.  These molecular biology techniques combined with novel biology concepts will serve me well both in my future Biology coursework at Brandeis and in my future pursuits in and after medical school. Who knows, I may even end up a practicing Endocrinologist and participating in BAT thermogenesis research!  Only time will tell.

– Josh Lepson

[i] Brandeis University Hiatt Career Center. 2017. World of Work (WOW) Summer Internship Blog: Harnessing Science for the Common Good. Accessed on July 2.

Harnessing Science for the Common Good

[ii] Beth Israel Deaconess Medical Center. 2017. Endocrinology, Diabetes and Metabolism. Accessed on July 2.

http://www.bidmc.org/Centers-and-Departments/Departments/Medicine/Divisions/Endocrinology.aspx

[iii] ThermoFisher Scientific. Basic Principles of RT-qPCR: Introduction to RT-qPCR. Accessed on July 2.

https://www.thermofisher.com/us/en/home/brands/thermo-scientific/molecular-biology/molecular-biology-learning-center/molecular-biology-resource-library/basic-principles-rt-qpcr.html

[iv] ThermoFisher Scientific. Overview of Western Blotting. Accessed on July 2.

https://www.thermofisher.com/us/en/home/life-science/protein-biology/protein-biology-learning-center/protein-biology-resource-library/pierce-protein-methods/overview-western-blotting.html

[v] Olshansky, S.J., Passaro, D.J., Hershow, R.C., Layden, J., Carnes, B.A., Brody, J., Hayflick, L., Butler, R.N., Allison, D.B., Ludwig, D.S. 2005. A potential decline in life expectancy in the United States in the 21st century. N. Engl. J. Med. 352(11): 1138-1145.

[vi] Harms, M., Seale, P. 2013. Brown and beige fat: development, function and therapeutic potential. Nat. Med. 19(10): 1252-1263.

[vii] The Jackson Laboratory. B6.Cg-Lepob/J. Accessed on July 2. https://www.jax.org/strain/000632

[viii] Bartelt, A., Heeren, J. 2014. Adipose tissue browning and metabolic health. Nat. Rev. Endocrinol. 10(1): 24-36.

[ix] ThermoFisher Scientific. Pierce™ BCA Protein Assay Kit. Accessed on July 2.

https://www.thermofisher.com/order/catalog/product/23225

Last Days at the Pediatric High BMI Clinic

My internship at the Pediatric High BMI Clinic at the Kentucky Children’s Hospital ended with a four-hour program named Fun Day on Friday, August 10th 2012. As a Biology and HSSP major, my main academic goal was to apply my knowledge from the classroom to a clinical setting by interacting with patients and various health care professionals. Every morning I walked into the clinic with an open mind and a positive attitude. The first thing I did was check the schedule of appointments for the day. When patients arrived, sometimes I helped the nurses with triaging the patients, such as taking their height, weight, waist circumference, and blood pressure. Most of time I looked over patients’ family and medical history, calculated their body mass index, and plotted the data on the growth chart to monitor their development. I also examined patients’ dietary and physical activity level with the dietitian in order to conduct nutritional counseling. From observing the clinic staff’s interaction with the patient and participating in medical case discussion following each patient’s visit, I learned that obesity is a complicated illness with many factors. By collecting and analyzing surveys, data, and organizing the program Fun Day 2012, I realized that while it is important to educate the child about the importance of balanced nutrition and portion size, it is more essential to encourage his family members to provide physical and mentor support, and to foster a positive environment at home for healthy eating and weight loss. Additionally I learned that childhood obesity does not only result in medical comorbidities, overweight or obese children are often victims of bullying at school, which may further cause these children to develop emotional eating, low self-confidence, and even depression. This creates a vicious cycle that sustains the childhood obesity epidemic.

Fun Day 2012 – Bike riding with the Bluegrass Cycling Club
Fun Day 2012 – How to pack a budget-friendly, well-balanced lunch for school

My summer at the Pediatric High BMI Clinic has fulfilled my learning goals and exceeded my expectations. I will return to Brandeis with a new perspective on health and illnesses. I will further reflect upon my experience in the HSSP89 Internship Analysis course. In the future, I would like to continue learning about obesity and related illnesses and possibly take courses on nutrition and dietetics. After seeing how I, as merely an undergraduate student, can contribute in making a difference in people’s lifestyles, I became even more enthusiastic and motivated  to pursue a career in healthcare and medical practice. During the entire course of my internship, I felt like I was a piece of a puzzle that fit right in. I can picture myself working in a clinical or hospital setting, shuffling in and out of examination rooms, or sitting at a desk making the ideal treatment plans for my patients.

Group picture with the clinic staff and a volunteer

I would recommend this internship at the Kentucky Children’s Hospital at the University of Kentucky (UK). UK is a large yet structured organization that houses many different departments. There are countless opportunities available. The student would just need to do his research to target the department of interest and actively contact the appropriate offices. For students who are interested in an internship in the healthcare industry, I would advise them to keep an open mind. Every patient is different, and every case is unique. As long as your interest lies there, you will never be bored working in the field of healthcare. – Yan Chu, ’13