Immunometabolic Response, Stress and Metabolic Diseases

fat cells (obese_fat_cell.jpg.jpg)

Fat cells in an obese mouse have swollen up with stored lipids and become much larger. The purple dots between the cells are inflammatory cells and macrophages that cluster around dead and degenerated cells to engulf and digest them.

Studies in our lab and many others have clearly established that chronic, low-grade, sustained, systemic inflammation is a central feature of obesity and metabolic syndrome. This inflammatory response is distinct, appears to respond to intrinsic cues, is not resolved, involves a variety of immune and metabolic cells, and does not resemble the classical inflammatory paradigm. Importantly, it does not promote energy expenditure. We refer to this metabolic inflammation as “metaflammation”. While inflammation is critical part of normal tissue homeostasis and repair as an acute adaptive response, in the chronic time frame, both inflammation and metaflammation are damaging and can lead to a variety of pathological conditions, including diabetes.

We are interested in examining the molecular mechanisms leading to the emergence of these metaflammatory responses and how they are linked to metabolic homeostasis as well as disease. Our effort is targeted to major cell types and organs where inflammatory and metabolic pathways interface, such as adipose, liver tissue, and pancreas, as well as immune cells such macrophages, and metabolic cells, such as adipocytes, hepatocytes, and beta cells. In these systems and in genetic animal models, we explore the hormonal and metabolic signals that generate profound effects on systemic endocrine equilibrium. Some of the major pillars of our work are summarized below:

Nutrients, stress, and metaflammation:

The ability of nutrients to trigger inflammation raises an important question regarding the control of overt inflammation during physiological fluctuations in nutrient and energy exposure. In search of molecules that prevent such aberrant responses, we identified six-transmembrane protein of prostate 2 (STAMP-2), which modulates nutrient-induced inflammatory responses, particularly in adipocytes. STAMP2 expression in the liver is regulated by feeding and fasting cycles, and the absence of this gene results in visceral adipose tissue inflammation, stress responses, insulin resistance, and atherosclerosis. In addition, we recently showed that STAMP2 regulates inflammatory responses in macrophages. We are currently investigating the molecular function and the underlying mechanisms of Stamp-2 and studying its target cells and organs as well as the signals that engage these adaptive response pathways.

Metabolic stress gives rise to a cascade of signaling events in the organs that are critical for homeostasis. Obesity-related activation of the inflammatory and stress serine/threonine kinases, such as JNK, and the consequent inhibition of insulin receptor signaling via phosphorylation of the insulin receptor substrate (IRS-1) occur in both experimental and human metabolic disease such as obesity, and are important and common mechanisms of insulin resistance and metabolic decline. Indeed, deletion of the JNK genes or inhibition of JNK activity in mice confers significant protection against obesity and diabetes. There is also biochemical as well as genetic evidence that JNK activation is linked to diabetes in humans. Currently, we are investigating the metabolic signals and stresses that give rise to JNK activation and exploring the potential of blocking JNK function to treat or prevent diabetes, obesity, and atherosclerosis, and the tissue specific actions of JNK, particularly in adipocytes.

In exploring these avenues, our recent studies indicated that the double stranded RNA dependent protein kinase PKR is a key modulator of chronic metabolic inflammation, insulin sensitivity and glucose metabolism in obesity and a key mechanism involved in JNK activation in this context. Activated in response to various stresses including pathogens, lipids and metabolites, PKR engages immune response pathways, phosphorylates and inhibits components of the insulin signaling pathway, with additional implications to protein translation and organelle function. We and others found that mice deficient in PKR are protected from the metabolic defects associated with diet induced obesity. Importantly, PKR is also significantly activated in human disease in adipose and liver tissue. We are currently investigating the role of PKR in other metabolic diseases, and refining our understanding of the molecular signals that modulate its function. We are also pursuing synthetic and naturally occurring ligands of PKR with the goal of understanding the signals that give rise to metaflammation and identifying unique molecular entities for therapeutic targeting of this dual-enzyme. Hence, this aspect of the project carries implications for both sensing and responding to nutrients and stress signals in metabolic homeostasis and disease.

Endoplasmic reticulum and organelle homeostasis in metabolism:

The endoplasmic reticulum (ER) is a critical organelle responsible for the synthesis, maturation, folding and transport of all secreted and transmembrane proteins and is the site for lipid synthesis and packaging. The ER meets the fluctuations in cellular demand by mounting an adaptive response called “unfolded protein response” or UPR. The UPR increases ER folding capacity and decreases the global translation rate while simultaneously activating a transcriptional program to supply the ER with the necessary components to re-establish equilibrium. However, if the cellular demand is unabated, chronic activation of the UPR can induce maladaptive, pro-apoptotic pathways.

Obesity leads to ER stress in metabolically sensitive tissues such as adipose, liver, and pancreatic islets. Through activation of JNK, PKR, and other stress signaling pathways, ER stress is linked with regulation of insulin action and glucose and lipid metabolism and also integrates well with other activities of our group. Interestingly, these molecular mechanisms are relevant to both type 1 and type 2 diabetes, potentially through their activity in immune and beta cell interactions. Currently, we are exploring the molecular mechanisms leading to ER stress in obesity and investigating the role of different UPR branches in metabolic homeostasis. We are exploring the endogenous modulators of ER stress, and developing strategies for chemically and genetically targeting these pathways for novel therapeutic opportunities against metabolic diseases. In this regard, we have discovered that two independent chemicals that possess chemical chaperon activity and relieve ER stress, PBA and TUDCA, are potent anti-diabetics in preclinical models. These compounds have since been shown to be active in many independent studies and in other models. There are also some proof-of-principle studies conducted in humans to support the viability of utilizing these and similar strategies for the treatment of human disease.

We are also conducting systematic studies to explore the unique metabolic aspects of ER function and UPR and perform whole-genome screens to identify the molecules involved in these aspects of ER biology. For example, these studies have led us to demonstrate that the increase in ER stress in the obese condition is in part related to the defects in the cellular recycling system autophagy. Currently, an important additional focus in the lab is to explore the proximal and distal molecular links between ER function, UPR, and inflammatory pathways. Our systematic analysis of ER components also led to the important observation that one of the principal mechanisms that disturb ER function in obesity is related to changes in lipid metabolism and composition that influences ER membranes and results in alterations ER calcium homeostasis. Most recently, in pursuing this mechanism, we discovered abnormal interactions between ER and mitochondria in the context of metabolic disease. These observations also indicate that defects seen in both of these organelles in metabolic disease may arise from a common platform and may both involve disturbances of calcium homeostasis. We hope to identify the molecular mechanisms of the crosstalk between inflammatory and metabolic pathways or integration of nutrient and pathogen sensing pathways. This finding highlights additional molecular pathways that may be targeted in the search for novel therapeutics for metabolic disease.

Suggested reading from our lab:

Engin F, Yermalovich A, Nguyen T, Hummasti S, Fu W, Eizirik DL, Mathis D, Hotamisligil GS. Restoration of the unfolded protein response in pancreatic β cells protects mice againt type 1 diabetes. Science Transl Med., 2013 Nov 13;5(211). Abstract | PDF

Gregor MF, Misch ES, Yang L, Hummasti S, Inouye KE, Lee AH, Bierie B,Hotamisligil GS. The role of adipocyte XBP1 in metabolic regulation during lactation. Cell Reports 2013, 3(5):1430-9 Abstract | PDF

Fu S, Fan J, Blanco J, Gimenez-Cassina A, Danial NN, Watkins SM, Hotamisligil GS. Polysome profiling in liver identifies dynamic regulation of endoplasmic reticulum translatome by obesity and fasting. PLoS Genetics, 2012, 8(8):e1002902. Abstract | PDF

Fu S, Watkins SM, Hotamisligil GS. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab., 2012 May 2;15(5):623-34. Abstract| PDF

ten Freyhaus H, Calay ES, Yalcin A, Vallerie SN, Yang L, Calay ZZ, Saatcioglu F, Hotamisligil GS. Stamp2 controls macrophage inflammation through nicotinamide adenine dinucleotide phosphate homeostasis and protects against atherosclerosis. Cell Metabolism 2012, 16(1):81-9. Abstract | PDF

Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annual Reviews Immunology, 2011. Abstract | PDF

Fu S, Yang L, Li P, Hoffman O, Dicker L, Hide W, Lin X, Watkins, SM, Ivanov A, Hotamisligil GS. Aberrant lipid metabolism disrupts calcium homeostasis causing liver ER stress in obesity. Nature, 2011, 473; 528-531. Abstract | PDF

Yang L, Li P, Fu S, Calay ES, Hotamisligil GS. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metabolism 2010, 11(6):467-78. Abstract | PDF

Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, Gorgun CZ, Hotamisligil GS. Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell 2010, 140(3):338-48. Abstract |PDF

Vallerie SN, Hotamisligil GS. The role of JNK proteins in metabolism. Science Translational Medicine, 2010. Dec 1;2(60):60rv5. Abstract | PDF

Gregor MF, Hotamisligil GS. Adipocyte Stress: The endoplasmic reticulum and metabolic disease. J of Lipid Research 2007, 48(9): 1905-14. Abstract | PDF

Wellen K, Fucho R, Gregor MF, Furuhashi M, Morgan C,Lindstad T, Vaillancourt E, Gorgun CZ, Saatcioglu F, Hotamisligil GS. Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis. Cell 2007, 129:537-548. Abstract | PDF

Hotamisligil, GS. Inflammation and Metabolic Disorders. Nature 2006, 444(7121):860-7. Abstract | PDF

Tuncman G, Erbay E, Hom X, De Vivo I, Campos H, RimmEB, Hotamisligil GS. A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, andcardiovascular disease. Proc Natl AcadSci USA 2006, 103(18):6970-5. Abstract | PDF

Wellen KE, Hotamisligil, GS. Inflammation, stress and diabetes. J Clin Invest 2005, 115:1111-1119. Abstract | PDF

Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E,Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action and type 2 diabetes. Science 2004, 306:457-61. Abstract |PDF

Hirosumi, J, Tuncman, G, Chang, L, Gorgun, CZ, Uysal, KT,Maeda, K, Karin, M, Hotamisligil, GS. A central role for JNK in obesity and insulin resistance. Nature 2002, 420:333-336. Abstract | PDF

Uysal KT, Wiesbrock SM, Marino MW and Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF function. Nature 1997 Oct 9; 389(6651): 610-614. Abstract | PDF