Louis G. D’Alecy Professorship of Physiology Liangyou Rui, PhD Louis G. D'Alecy Professorship of Physiology
O
n 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/
12
Physiology Matters
L to R: Dr. Liangyou Rui (Louis G. D'Alecy Professor, MIP), Dr. Santiago Schnell and Dr. Loius D'alecy (Professor Emeritus, MIP)
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,
