Ezra Burstein, M.D., Ph.D., a Professor and Chief of Digestive and Liver Diseases, and colleagues recently published the results of an investigation into the molecular organization of essential regulators of endosomal recycling, a process required for normal functioning of all cells. The study, which appears in the December issue of Nature Structure and Molecular Biology, builds on nearly two decades of work in the Burstein Lab, starting with the discovery of a family of proteins known as COMMD.

We asked Dr. Burstein to summarize the research and its significance.

In this study, we report the molecular organization of critical regulators of endosomal recycling, a process required for normal function of all cells. The plasma membrane of the cell is an essential barrier between the environment and the inside machinery of the cell. It is not only a membrane, but it includes a number of essential proteins including receptors, transporters, channels, and myriad other factors, which represent nearly 11% of all proteins in human cells. Normal cell function requires a constant flux of membranes from the cell surface to intracellular vesicles known as endosomes. Plasma membrane proteins are included in these membranes. From endosomes, these proteins are sent back to the plasma membrane for recycling or routed to lysosomes for degradation. Given the indispensable functions of many plasma membrane proteins, the process of endosomal recycling is essential to cellular homeostasis. The paper describes the molecular organization of the Retriever complex, an essential regular of endosomal recycling, as well as its closely associated partner, the COMMD/CCDC22/CCDC93 or CCC complex. With 16 distinct protein subunits, this structure is complex and deciphering its organization allows us for the first time to begin to understand how this system works at the molecular level. 

Many aspects of normal health are dependent on normal function of the Retriever and CCC complex. For example, inherited mutations damaging components of this system lead to elevated cholesterol, alterations in copper handling in the body, and altered intrauterine development resulting in a congenital condition known as Ritscher-Schinzel syndrome. As part of the studies published, the group also reported for the first time that some cancer types frequently harbor mutations that inactivate the Retriever complex, resulting in significant changes in plasma membrane proteins. The study is the result of a close partnership with Dr. Stone Chen, Associate Professor at Iowa State University, as well as Dr. James Chen, Professor in the Department of Biophysics at UT Southwestern, co-corresponding authors on the paper. This work builds on nearly two decades of work in the Burstein lab, starting with the discovery of the family of proteins known as COMMD proteins nearly 20 years. AlphaFold, a computational method based on artificial intelligence that can predict protein folding based on amino acid sequences, as well as the advent of cryogenic electron microscopy, made these studies possible.

New research findings published in the Journal of Clinical Investigation could potentially impact all diseases for which exercise may be used as a treatment or preventive method, including obesity, depression, type 2 diabetes, and cancer.

We asked Jeffrey Zigman, M.D., Ph.D., a Professor in the Division of Endocrinology, and his colleagues in the Center for Hypothalamic Research, to explain his team’s findings.

In one sentence, why is this research noteworthy?

Our research demonstrates for the first time that activation of ghrelin-responsive neurons in the mediobasal hypothalamus is required for the normal feeding response to high intensity interval exercise and the usual amount of running exhibited during an exercise endurance protocol.

What diseases do the findings potentially impact?

This potentially impacts all diseases for which exercise may be used as a treatment or a preventative method, including obesity, depression, type 2 diabetes, and cancer.

What are the top three takeaways from the study/research?

1. Inhibition of ghrelin-responsive neurons in the mediobasal hypothalamus (a region of the brain) suppresses food intake following a high-intensity interval exercise protocol. 
2. Inhibition of ghrelin-responsive neurons in the mediobasal hypothalamus (a region of the brain) reduces running distance in an exercise endurance protocol.
3. High intensity interval exercise increases the expression of GHSR, which serves as the receptor for ghrelin, in the mediobasal hypothalamus.

Does this build on previous findings from you or your lab, or other researchers at UTSW?

Yes – Previous collaborative work from the Zigman and Elmquist labs implicated the orexigenic hormone ghrelin as a mediator of exercise endurance and the feeding response post-exercise. Specifically, plasma ghrelin levels were shown to double in mice when they are submitted to high-intensity interval exercise. Also, mice lacking GHSR were shown to exhibit decreases food intake following high intensity interval exercise and a diminished running distance during a longer exercise endurance protocol. Previous work by the Elmquist lab has identified the ventromedial hypothalamus (which helps comprise the mediobasal hypothalamus) as a key brain region regulating the metabolic responses to exercise. Further, previous work by the lab of Kevin Williams had shown that exercise induces changes in the organization of neuronal circuits within the arcuate hypothalamic nucleus (which also helps comprise the mediobasal hypothalamus).

Are there any distinctive tools, technology, training, grants, development initiatives or state or federal funding such as NIH that we should acknowledge?

Most importantly, there are two key funding sources listed: one is the program project grant (P01) of which Joel Elmquist is PI and I (Zigman) and Kevin Williams are Project Leaders.  Also, funding of Om Singh (my postdoc) by the OBI Sprouts program. This work was supported through research grants from the NIH (P01 DK119130 to Joel Elmquist and R01 DK119341 to J.M.Z.), the Diana and Richard C. Strauss Professorship in Biomedical Research (to J.M.Z.), the Mr. and Mrs. Bruce G. Brookshire Professorship in Medicine (to J.M.Z.), and the Kent and Jodi Foster Distinguished Chair in Endocrinology, in Honor of Daniel Foster, M.D. (to J.M.Z.), and the Peter O’Donnell Jr. Brain Institute (OBI) Sprouts Program (to O.S.).

How does this advance the field?

This research expands our understanding of how the ghrelin system responds to exercise and where ghrelin acts in the brain to regulate food intake after exercise and to regulate exercise endurance. 

How does this tie into/advance toward clinical solutions for patients?

This research helps us to better understand how the gut-brain axis links exercise to metabolism. As exercise has been shown to have numerous health benefits across a wide spectrum of diseases, this new insight into the hormonal-neuronal interactions mediating eating after exercise and exercise endurance hopefully can eventually be harnessed to improve/highlight those benefits.

How do UTSW’s education, clinical care, or other research missions tie into this research?

This research was conducted within UT Southwestern’s Center for Hypothalamic Research, which was established in 2006 to bring together scientists interested in understanding the mechanisms by which the hypothalamus regulates eating, body weight, blood glucose, and related metabolic processes. The Center is unique among academic institutions in that it is the only one with a primary focus on the hypothalamus. By studying the hypothalamus plus interconnected brain regions, peripheral organ systems, and hormonal networks along the gut-brain axis, we hope to better understand the pathogenesis of obesity, diabetes, and related metabolic/mood disorders. 

This research also is aligned with the UT Southwestern’s Nutrition and Obesity Research Center’s mission to support research infrastructure, enrichment programs, and collaborative activities for investigators conducting research in the causal factors of nutrition and obesity-related health problems, including consequences, prevention, and alleviation.

Further, this research has been facilitated by the mission of the Endocrinology Division at UT Southwestern, with its diverse faculty whose expertise spans the spectrum of endocrine diseases, including obesity and diabetes.

Dr. Zigman holds the Kent and Jodi Foster Distinguished Chair in Endocrinology, in Honor of Daniel Foster, M.D.; the Mr. and Mrs. Bruce G. Brookshire Professorship in Medicine; and the Diana and Richard C. Strauss Professorship in Biomedical Research.