The major research focus at LMM is to understand the regulation of metabolic homeostasis by using molecular physiology and molecular imaging approaches. These include metabolic phenotyping and mechanistic studies on the contributions to the overall metabolic state and health by various peripheral tissues and organs, such as pancreas, muscle, liver, heart and adipose tissue.
These programs provide a systemic understanding of whole body metabolic homeostasis, which is also extended to include interactions between the brain and these peripheral metabolic organs (see diagram below). As significant diseases, such as diabetes, CVD and neurological diseases, develop when these processes become impaired or dysregulated, such understanding at the physiology state provides opportunities to discover intervention strategies in treating the associated diseases, which may also have broader implications in the natural and pathological aging process.
Furthermore, we are in the process of developing a focused neuroscience program that dovetails the existing research strength in metabolic homeostasis at LMM to focus on the discovery of peripheral factors in modulating the central nervous system (CNS). We envisage that the converging research efforts in these areas will help provide molecular understanding of neurological disease development, especially those that are of higher risk in people with diabetes and metabolic disorders.
Among the major research projects, a key topic in the lab is to understand the role of regulated exocytosis in relation to diabetes development. Specific projects include identifying regulatory proteins for insulin secretion and GLUT4 exocytosis, and how these proteins are affected under relevant signaling pathways (e.g. GLP-1 and insulin), which in turn affect insulin secretion and GLUT4 exocytosis, respectively. We also investigate the molecular regulation of secretory granule biogenesis, in particular insulin and glucagon granules. A second key topic is to understand the cellular mechanism of adipogenesis, especially in the context of the lean diabetic Asian phenotype. A third research area is to understand metabolic changes in an emerging diabetic complications, liver cancer, and to identify novel pathways for therapeutic interventions.
Dual functions of Syt7 in the regulation of insulin secretion. Syt7 serves as a major Ca2+-sensor for GSIS (in its non-phosphorylated form) and mediates the potentiation of GSIS by incretins in its phosphorylated form. (Gustavsson et al. PNAS 2008, Wu et al., PNAS 2016)
Tmod3 is a novel Akt2 substrates in regulating actin remodeling and the ensuing GLUT4-containing vesicle exocytosis. (Lim et al., Nature Comm. 2015)
BIG3 is an essential regulator of insulin granule biogenesis (Li et al., EMBO Reports 2014)
Extensive actin cytoskeletal remodeling during adipocyte development (adipogenesis), but not during lipogenesis (Yang et al., Human Molecular Genetics 2014)