Inflammation, 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 others have clearly demonstrated that chronic inflammation is a central feature of obesity and metabolic syndrome. This inflammatory response is distinct, appears to respond to intrinsic cues, and does not resemble the classical inflammatory paradigm. New names have been suggested to describe this phenomenon including “metaflammation” or “paraflammation”.

We are interested in examining the molecular mechanisms leading to the emergence of these inflammatory 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 and liver tissue as well as macrophages. In these systems and in genetic animal models, we explore the hormonal and metabolic signals that generate profound effects on systemic endocrine equilibrium.

Obesity-related activation of the serine/threonine kinases, such as JNK, and the consequent inhibition of insulin receptor signaling via phosphorylation of the insulin receptor substrate (IRS-1), is a central mechanism of insulin resistance. Indeed, deletion of the JNK genes in mice confers dramatic protection from obesity and diabetes. There is also genetic evidence that JNK activation is linked to type 2 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.

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 of Stamp-2 and studying its target cells and organs.

In addition, our recent work suggests that the double stranded RNA dependent protein kinase PKR is a key modulator of chronic metabolic inflammation, insulin sensitivity and glucose metabolism in obesity. Activated in response to various stresses, PKR phosphorylates and inhibits components of the insulin signaling pathway. We found that mice deficient in PKR are protected from the metabolic defects associated with diet induced obesity. We are currently investigating the role of PKR in other metabolic diseases, and refining our understanding of the molecular signals that modulate its function.

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. 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. We hope to identify the molecular mechanisms of the crosstalk between inflammatory and metabolic pathways or integration of nutrient and pathogen sensing pathways. In addition, we recently showed that the increase in ER stress in the obese condition is in part related to the downregulation of the cellular recycling system autophagy. This finding highlights additional molecular pathways that may be targeted in the search for novel therapeutics for metabolic disease.

Suggested reading from Hotamisligil Lab:

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

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

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, Furuhashi M, Fucho R, Hotamisligil GS. A predominant role of JNK activity in the stromal elements in regulating systemic insulin sensitivity. PLoS 2008, 3 (9): 1-11. 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