Jürgen Wess, Ph.D.

Research Goal

The ultimate goal of this work is to identify novel drug targets for the more effective treatment of various human diseases, including type 2 diabetes (T2D) and obesity.

Current Research

The superfamily of G protein-coupled receptors (GPCRs) represents the largest group of cell surface receptors found in nature. Following activation by extracellular ligands, such as neurotransmitters, hormones, or sensory stimuli, GPCRs regulate numerous important physiological functions. GPCRs are the targets of ~35% of all therapeutically used drugs, indicative of their preeminent clinical relevance. In general, an agonist-occupied GPCR interacts with specific sets of heterotrimeric G proteins, resulting in the activation of various intracellular signaling cascades.

Based on the structure and function of their alpha-subunits, heterotrimeric G proteins are subclassified into four major subfamilies: Gq/11, Gi/o, Gs, and G12/13. Activated GPCRs are recognized by a pair of cytoplasmic proteins known as beta-arrestin-1 and -2 which mediate GPCR desensitization but can also function as signaling molecules in their own right. A main goal of my section is to elucidate the importance of distinct GPCR signaling pathways in maintaining whole-body glucose and energy homeostasis. This work is of great general importance since obesity and type 2 diabetes have emerged as major threats to human health worldwide. During the past few years, my lab has addressed the following major questions:

• What are the in vivo metabolic consequences of activating distinct GPCR/G protein signaling pathways in different metabolically important cell types?
• What are the physiological and pathophysiological roles of beta-arrestins expressed by different cell types critical for glucose and energy homeostasis?
• How can the outcome of these studies guide future drug development efforts?

Approaches

Designer GPCRs referred to as DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) have emerged as powerful tools to study the physiological relevance of distinct GPCR signaling pathways in specific cell types in vivo. Work carried out in several labs, including my own, has led to the development of DREADDs that are selectively linked to only one of the four major subclasses of G proteins. Structurally, the most commonly used DREADDs are mutant muscarinic acetylcholine receptors that cannot bind acetylcholine, the endogenous muscarinic receptor agonist. However, DREADDs can be activated with high potency by small synthetic drugs (e.g., clozapine-N-oxide (CNO) or deschloroclozapine (DCZ)), which are otherwise pharmacologically inert.

Over the past decade, we have used DREADD technology to study the in vivo metabolic roles of activating distinct G protein signaling pathways operating in specific peripheral and central cell types. Specifically, we generated mutant mice that expressed different DREADDs in several metabolically important cell types, including adipocytes, hepatocytes, pancreatic beta-cells, enteroendocrine K-cells, skeletal muscle cells, and distinct neuronal subpopulations of the hypothalamus. Cell type-selective DREADD expression was achieved by generating genetically engineered mice or via virus-based delivery techniques. CNO or DCZ treatment of the DREADD mutant mice results in the selective stimulation of distinct sets of G proteins only in the DREADD-expressing cells. This approach makes it possible to assess the in vivo metabolic consequences of activating a distinct GPCR signaling pathway in a specific cell type. Such studies cannot be performed with ligands targeting endogenous GPCRs which, as a general rule, are expressed by multiple tissues and cell types. In parallel, we also generated mice that lacked specific functional classes of G protein α-subunits in the same cell types targeted by DREADD technology. Based on the metabolic phenotypes displayed by the various mutant mouse lines, we also identified endogenously expressed GPCRs that could serve as targets for novel antidiabetic and anti-obesity drugs.

The ultimate goal of this research is to identify new targets for the development of novel drugs useful for the treatment of T2D, obesity, and related metabolic disorders.

Applying our Research

Type 2 diabetes and obesity have emerged as major threats to human health in the 21st century. It is likely that the proposed studies will identify novel biological targets for the treatment of these and related pathophysiological conditions. Moreover, a better understanding of GPCR structure and function should lead to new strategies aimed at improving the pharmacotherapy of many important human diseases.

Need for Further Study

Areas in this field that require further study include GPCR structure and function, mechanisms of ligand binding, and the physiological and pathophysiological roles of distinct GPCRs and GPCR signaling pathways in specific cell types in vivo.

Research in Plain Language

My laboratory focuses on the analysis of G protein-coupled receptors (GPCRs), one of the largest protein families found in nature. GPCRs are receptors located on the surface of cells. Many important chemicals in the body—including neurotransmitters, which carry signals from cell to cell, and hormones, which carry signals from one part of the body to another—bind to GPCRs. GPCRs mediate the functions of these critical chemical messengers. Two striking facts illustrate the essential contributions of GPCRs: (1) The entirety of our hereditary information (the human genome) contains approximately 800 distinct GPCR genes, corresponding to 3–4% of all human genes; (2) 30–40% of medications act on specific GPCRs.

One major focus of my lab is to understand how GPCRs function at the molecular level because such knowledge can lead to the development of better treatments. As indicated by the name, GPCRs are linked to G proteins, which act as a molecular switch that is biochemically turned “on” or “off” within the cell. We use different molecular, genetic, and biochemical strategies to better understand how GPCR function is regulated in different cell types.

Currently, the major goal of my lab is to identify GPCRs that can serve as novel targets for the treatment of type 2 diabetes and obesity. To achieve this goal, we are using a new strategy that allows us to activate distinct classes of G proteins in specific cell types in live mice including pancreatic beta- and alpha-cells; cells in the liver, skeletal muscle, and hypothalamus; and a brain structure that represents a major regulator of blood glucose levels, food intake, and body weight. Specifically, we are expressing modified GPCRs with distinct ligand binding and signaling properties in a cell type-specific fashion in transgenic mice. We also analyze mutant mice in which we inactivated certain GPCR genes or genes coding for GPCR-associated proteins (G proteins, beta-arrestins, etc.) in cell types important for maintaining normal blood glucose levels and body weight. The ultimate aim of this research is to identify new biological targets for the development of novel treatments for type 2 diabetes and obesity, two major metabolic disorders that affect a large percentage of individuals worldwide.