The Kralli Laboratory

Research

INTRODUCTION

Metabolic homeostasis requires efficient adaptation of the body’s metabolism to energetic challenges. In response to changes in the environmental temperature, nutrient state, physical activity, and/or immune system, cells adapt their energy homeostasis programs in a cell-type specific manner. Healthy adaptive responses consist of appropriate switches of signals that initiate a response to the emerging challenge, as well as prompt an end of the response once the challenge is met. Post-translational modifications are essential for immediate and fast response to signals, while transcriptional regulation of gene expression is important for determining the repertoire of proteins available for fast signaling relays, as well as long-term adaptive responses that prepare for meeting future similar energetic challenges. Deregulation of adaptive responses can lead to diminished capacity to survive challenges (e.g. when responses are inefficient) and/or metabolic disease (e.g. when responses are inefficient, induced at inappropriate times or unnecessarily prolonged). Understanding the transcriptional networks that determine the ability of cells to sense and respond to energetic challenges and stressors will provide insights into how these pathways become deregulated in the states of obesity and/or diabetes, as well as open new avenues for therapeutic intervention in metabolic disease.

Our studies focus on the Estrogen-Related Receptors (ERRα, ERRβ, and ERRγ), which we use as an entry point to the study of the regulatory / transcriptional networks that are important for adaptation in adipose tissue and in skeletal muscle, in response to changes in environmental temperature, physical exercise and/or diet. In past studies, we have shown that ERRs, and in particular ERRα, co-ordinate gene expression programs that regulate mitochondrial biogenesis and oxidative capacity.  Our current studies build on this past work, using mouse models with genetically modified loci for ERRs (floxed alleles) and dissecting the unique and shared roles of ERRs in adipose tissue and in skeletal muscle. We are also identifying novel mechanisms that regulate ERR activity, as well as new important downstream effectors of ERRs, thereby expanding the network of regulators of mitochondrial oxidative function. Our studies identify and probe new avenues for therapeutic intervention in states where oxidative metabolism and tissue function are compromised, such as insulin resistance and type 2 diabetes, disease-associated muscle atrophies and age-related degenerative diseases.

THE ROLE OF ADIPOSE ESTROGEN-RELATED RECEPTORS IN ENERGY HOMEOSTASIS

Obesity, obesity-related diseases (e.g., type 2 diabetes, dyslipidemia, cardiovascular disease), and the related health care costs are increasing world-wide. Pharmacological approaches that safely prevent or reduce obesity can have a significant impact on human health and medical costs. Obesity is caused by an excess of caloric intake compared to energy expenditure. While pharmacological approaches have so far focused primarily on decreasing energy intake, strong arguments suggest that approaches aimed at increasing energy expenditure can also be successful. Notably, small increases in energy expenditure can lead to weight loss, as seen with the use of uncouplers. Elucidation of the mechanisms that control energy expenditure may lead to safe approaches for treating obesity and obesity-related diseases.

Adipose tissue is important for energy balance. White adipose tissue (WAT) stores excess energy in the form of lipids, while brown adipose tissue (BAT) dissipates energy via thermogenesis. In rodents, defective BAT activity leads to obesity and metabolic disease; conversely, experimental increases in BAT are associated with a lean and metabolically healthy phenotype. In adult humans, the presence of BAT correlates with adiposity and BMI, suggesting that active BAT protects from obesity. Brown-like adipocytes expressing the uncoupling protein Ucp1, which generates heat by dissipating the mitochondrial proton gradient, also develop within WAT, in response to physiological and/or pharmacological stimuli. These brown-like adipocytes likely contribute to whole body energy expenditure. Thus, understanding the mechanisms that determine the development and activity of BAT and brown-like adipocytes in WAT is important for devising strategies that enhance energy expenditure in humans.

To elucidate the roles of adipose ERRs in energy homeostasis, we have generated  mouse models that lack ERRs specifically in BAT and WAT. Studies of these mouse models provide novel insights into the complementary and antagonistic roles of ERRs in energy homeostasis, as well as into regulators that act together with ERRs in controlling adipocyte metabolic homeostasis. We expect our studies to elucidate how ERRs affect energy balance, and define their potential as therapeutic targets. By expanding the network of ERR regulators and effectors in adipose tissue, our studies also suggest new targets and avenues for intervention in diseases that can benefit from increases in energy expenditure, such as obesity and obesity-related diseases.

ESTROGEN-RELATED RECEPTOR PATHWAYS IN SKELETAL MUSCLE

Skeletal muscle plays key roles in glucose and lipid homeostasis, and contributes to whole body energy expenditure. Poor physical fitness is a risk factor for developing type 2 diabetes, while exercise is an effective way to improve insulin sensitivity. In response to repeated exercise, muscle undergoes metabolic, contractile and morphological adaptations that improve muscle performance (i.e. ability for endurance exercise, strength, and metabolic flexibility). The long-term adaptations and improvements depend on the type of exercise and rely on signaling pathways that lead to changes in gene expression. Elucidation of the regulatory and transcriptional networks that determine adaptive responses in skeletal muscle is important for finding new ways to target muscle for improving metabolic health, and to develop therapeutic approaches for chronic disease - associated or injury-caused muscle atrophies, and age-related muscle function loss.

To elucidate the roles of muscle ERRs, we have generated  mouse models that lack ERRs specifically in skeletal muscle. Studies of these mouse models show that ERRs are collectively essential for muscle fitness and the capacity for exercise. We are defining the cellular and physiologic functions of specific ERRs in skeletal muscle, at the basal state and in adaptive responses to endurance exercise. We are also elucidating the mechanisms by which ERRs control muscle oxidative metabolism, and in particular addressing the role of a novel ERR effector, Perm1, for muscle mitochondrial function. Our studies provide novel insights into regulatory mechanisms that enable and shape skeletal muscle adaptive responses to endurance exercise, and inform new avenues for therapeutic intervention in states where oxidative metabolism and muscle function are compromised, such as insulin resistance and type 2 diabetes, disease-associated muscle atrophies and age-related muscle degeneration.