Diabetes and Obesity Genetics. The Soukas Laboratory in the Center for Human Genetic Research and the Diabetes Unit at the MGH seeks to understand the pathogenesis of obesity and diabetes, and to identify new therapeutic targets for these common, devastating diseases. Ancient, conserved thrifty metabolic programs were heavily selected for during times of feast or famine, but are highly disadvantageous in modern times of nutritional excess, contributing to obesity and cardiometabolic disease. Thrifty metabolism involves more efficient storage of energy in the form of body fat or triglycerides during well-fed times and judicious rationing of that energy during nutrient deprivation so as to permit extended periods of survival without food intake. The long-term goal of my laboratory is to define conserved genetic programs that lead to thrifty metabolic changes that may contribute to human obesity, type 2 diabetes and associated metabolic diseases. Our central hypothesis is that thrifty metabolic programs are encoded by ancient, genetic pathways conserved from C. elegans to humans.

The Soukas Lab operates at the nexus of vertebrate and invertebrate biology, leveraging the strengths of genetic discovery in the worm and the disease relevance of modeling in mice and human cells. We use classical genetics and state-of-the-art genomics in the invertebrate C. elegans in order to identify and explore genetic pathways involved in regulation of body fat stores, insulin signaling, and starvation defenses. We then model pathways using CRISPR genome editing technology to create disease models in human cell lines and to make genetically modified mice to study the disease relevance of findings from the worm. Our major projects are:

1) Identification of ancient, thrifty, starvation defense pathways involved in metabolic disease through unbiased genomics.
Through genome-wide RNAi screening in C. elegans for fat-regulatory genes, we have identified nearly 500 fat-regulatory genes. Two major, opposing pathways involved in protein homeostasis were also identified that are also seminally involved in starvation defenses and fat metabolism. The higher-order regulation of these protein homeostasis pathways and how they communicate to fat metabolism are areas of intense study in the lab. We also use genetic approaches in C. elegans, mice and human cells to determine the biological mechanisms by which the 500 fat-regulatory genes regulate starvation defenses and fat metabolism.

2) Identification of how the mTOR pathway regulates aging, metabolism, and starvation defenses.
The target of rapamycin (mTOR) pathway is a critical part of the insulin pathway regulating metabolism, lifespan, and stress resistance. We discovered that mTOR complex 2 acts through the kinase serum and glucocorticoid-induced kinase (Sgk) to regulate metabolism, growth, and lifespan, and this regulation is conserved to mammals. We are using genomic, epigenomic, and proteomic approaches to determine how mTOR and Sgk regulate glucose and lipid metabolism and lifespan in C. elegans and mouse models. In order to faciliate high-throughput examination of gene networks regulating lifespan, we have built a “lifespan machine” to dissect how mTOR complex 2 regulates aging.

3) Identification of conserved response pathways for the antidiabetic drug metformin.
Metformin is the most commonly prescribed drug for type 2 diabetes worldwide, and yet its molecular mode of action remains unclear. We are using the worm as a model to identify metformin response pathways, and involved in a collaboration where we interface our data with human genetic studies of metformin response genes. We have identified three major metformin response pathways which have conserved elements affecting metformin's ability to modulate blood glucose and prevent cancers.

Our unique combination of invertebrate and vertebrate genetics to approach obesity and diabetes allows science and discovery to move at a much faster pace, and we are actively engaged in bringing important findings to relevance in mammalian systems and ultimately humans.