Louis G. D’Alecy Professorship of Physiology

Liangyou Rui, PhD

Louis G. D'Alecy Professorship of Physiology

On January 30, 2020, the Department of Molecular and Integrative Physiology celebrated the inauguration of the Louis G. D’Alecy Collegiate Professorship in Molecular and Integrative Physiology and the installation of Liangyou Rui, Ph.D. as the first Louis G. D’Alecy Chair. Dr. Rui joined the U-M faculty in 2002 and has risen through the academic ranks in the Department of Molecular and Integrative Physiology, while also maintaining strong interactions with and appointments in the Department of Internal Medicine-Gastroenterology and Hepatology. Dr. Rui has a long history of commitment to obesity and metabolic disease research. His laboratory is dedicated to determining the mechanisms underlying obesity, type 2 diabetes, and fatty liver disease. To combat these diseases, Dr. Rui explains, it is imperative to understand disease development at both the molecular and the physiological (integrative) levels. Obesity arises from body energy imbalance. When energy intake (food intake) exceeds energy expenditure, excess energy is stored in fat, leading to obesity. The brain, particularly the hypothalamus, controls food intake and energy expenditure, thereby determining fat mass and body weight. Fat secretes a hormone called leptin. Leptin promotes weight loss by suppressing food intake and increasing energy expenditure. Leptin exerts its antiobesity action by activating its receptor LepRb in the brain. Counterintuitively, leptin therapy fails to reduce body weight in most obesity cases, because obesity patients develop resistance to leptin. In search of factors sensitizing leptin responses, Dr. Rui identified the protein SH2B1. In cell cultures, his team found that SH2B1 directly enhances leptin signal transduction. In mice, ablation of SH2B1 causes morbid obesity, type 2 diabetes, and fatty liver disease, resembling the symptoms of human obesity. These innovative findings have inspired investigations of human SH2B1. Genomewide association studies (GWAS) confirm that SH2B1 mutations are causally linked to obesity and metabolic syndromes in humans. Dr. Rui and his colleagues further discover that SH2B1 in LepRb neurons directly increases the ability of leptin to stimulate sympathetic nerves projecting to fat, particularly thermogenic brown fat and beige fat. This work defines a novel SH2B1/ sympathetic nervous system/fat axis that combats leptin resistance and obesity. Dr. Rui’s findings of the SH2B1/leptin signaling axis and the SH2B1/sympathetic nervous system/fat loop provide a framework for the future investigation of brain control of body weight and metabolism at the molecular level.

It has been long known that obesity is associated with chronic inflammation. Many cytokines induce insulin resistance, a hallmark of type 2 diabetes, linking inflammation to metabolic disorders. Notably, blood glucose levels are determined by a balance between insulin (decreasing blood glucose) and glucagon (increasing glucose levels). Dr. Rui and his team have identified NF-κB-inducing kinase (NIK), an inflammatory molecule, as a critical mediator between inflammation and aberrant glucagon actions. Liver NIK is highly elevated in obesity and increases the ability of glucagon to stimulate liver glucose production, thereby exacerbating progression of diabetes. In addition to regulating liver metabolism, Dr. Rui has also examined NIK actions in liver injury, inflammation, regeneration, and fibrosis, and has established a pivotal role of NIK in liver health and disease. Importantly, Dr. Rui and his collaborators have been designing novel therapeutic NIK inhibitors, aiming to develop new therapies for type 2 diabetes, nonalcoholic steatohepatitis (NASH), and alcoholic liver diseases using NIK inhibitors.

Recent research highlights a fundamental role of epigenetic reprogramming in health and disease. Histone methylation and acetylation profoundly influence gene expression, thereby shaping cell identity and functional states. Slug and Snail1, two related transcriptional regulators known to be involved in cancer metastasis,

L to R: Dr. Liangyou Rui (Louis G. D'Alecy Professor, MIP), Dr. Santiago Schnell (Chair, MIP) and Dr. Loius D'alecy (Professor Emeritus, MIP)

control gene expression by recruiting various treat alcoholic liver disease by therapeutic activation of epigenetic enzymes that catalyze histone brown and beige fat. modifications at target promoters/enhancers. In addition to his research, Dr. Rui has been strongly Dr. Rui and his group unveil, for the first time, committed to facilitating career development Snail1-elicited epigenetic reprogramming in opportunities for his trainees and junior faculty. Dr. white adipose tissue (WAT). Snail1-based Rui diligently guides his students and postdoctoral epigenetic modifications inhibit expression fellows in their research projects, and provides critical of lipolytic gene Atgl, thus restraining mentorships in paper and grant writings. Many of his lipolysis. Impaired Snail1 epigenetic activity trainees have successfully obtained highly competitive, increases lipolysis, resulting in increased lipid prestigious awards, including F31 Ruth L. Kirschsterin trafficking from WAT to the liver and fatty National Research Service Award from the NIH (Ph.D. liver disease. In hepatocytes, Dr. Rui’s team students), F32 Ruth L. Kirschsterin National Research found that Slug directly stimulates expression Service Awards (postdoctoral fellows), American Heart of lipogenic genes and de novo lipogenesis Association (AHA) Postdoctoral Fellowship Awards, by an epigenetic mechanism, contributing to Travel Grant Awards from the American Diabetes Dr. Liangyou Rui (Louis G. D'Alecy Professor, MIP), Dr. Santiago Schnell (Chair, MIP) fatty liver disease. In the brain, Slug-based Association (ADA), and Travel Grant Awards from the epigenetic reprogramming influences energy Endocrine Society. Many of his previous trainees have balance circuitry activity and obesity development. successfully developed their own independent research Of note, small molecule inhibitors of Snail1/Slug careers both in academic institutions and in industry associated epigenetic enzymes have been developed settings. On his naming as the first Louis G. D’Alecy to treat cancer. Dr. Rui’s findings raise an intriguing Collegiate Professor, Dr. Rui says, ‘Being named the possibility that these inhibitors may be repurposed to inaugural Louis G. D’Alecy Collegiate Professor was treat metabolic disease. overwhelming. I am truly honored and hope that I can live up to the exceptional example that Dr. D’Alecy Brown fat and beige fat have emerged as new continues to demonstrate for scientific discovery and targets for obesity treatment. Brown and beige fat professional citizenship’. are highly active in metabolism and burn glucose and fatty acids to produce heat, thereby conferring Dr. Louis G. D’Alecy was a full professor when Dr. Rui health benefits. Importantly, obesity is associated joined the faculty in the department. When he was a with decreased brown/beige fat in humans. Brown/ Ph.D. student in the Department of Physiology, Dr. Rui beige fat reactivation is an appealing strategy for even had Dr. D’Alecy’s as an instructor for his classes. Dr. combating obesity and metabolic disease. Exposure Rui’s daughter, Crystal Rui, who obtained her M.D. from to cold temperature is the most potent physiological the UM Medical School, also took Dr. D’Alecy’s courses. stimulator for brown and beige fat. Cold exposure Dr. D’Alecy has had exceptional scholarly achievements stimulates the sympathetic nervous system which and superior records of teaching, mentoring, and activates brown and beige fat. Interestingly, drinking service, and served as an inspirational role model alcohol also activates the sympathetic nervous system. for Dr. Rui. With respect to Dr. D’Alecy’s exceptional Dr. Rui discovered that drinking, like cold exposure, example, Dr. Rui states, ‘Since my earliest days in the robustly activates brown fat and beige fat. The Department, Dr. D’Alecy has been a role model as both brain senses alcohol and activates the sympathetic a creative and careful scientist and a committed and nervous system/fat axis. Remarkably, inactivation compassionate mentor’. The kind support of the family, of brown and beige fat dramatically augments fatty friends and colleagues of Dr. Louis G. D’Alecy ensures liver, liver injury, inflammation, and fibrosis upon that Dr. D’Alecy’s legacy will be honored in perpetuity. drinking. Mechanistically, brown and beige fat burn Through a generous endowment, the Louis G. D’Alecy fatty acids and block lipid trafficking into the liver, thus Collegiate Professorship will ensure that the research alleviating alcoholic fatty liver disease. Additionally, programs of deserving scientists at the University of brown and beige fat also secrete various factors that Michigan Medical School will be supported for years to protect against hepatocyte injury and death. Of note, come. • modest drinking has been widely believed to provide some health benefits. Dr. Rui’s findings indicate that recruitment and activation of brown and beige fat may explain drinking benefits. Hence, Dr. Rui’s findings provide a scientific foundation for a new strategy to