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Correcting altered immunological responses in obesity restores efficacy of targeted biologic therapy for inflammatory disease

ABSTRACT: Decades of work have elucidated cytokine signaling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic, and inflammatory diseases. More recent evidence indicates that obesity and other shifts in systemic metabolism can also influence the function of cells in the immune system, although the mechanisms and possible effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis (AD), we show that lean and obese mice mount strikingly different immune responses. Obesity converts the classical AD-associated type 2 T helper cell (TH2)-predominant disease into a more severe disease with prominent TH17 inflammation. In addition to this immunopathologic difference, we observed strikingly divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but significantly exacerbated disease in obese mice. Single-cell RNA sequencing (scRNA-seq) coupled with genome-wide binding analysis revealed decreased activity in nuclear receptor PPARg (peroxisome proliferator-activated receptor gamma) activity in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARg in T cells identified a novel function for PPARg as required for focusing the in vivo TH response towards a TH2-predominant state and preventing aberrant non-TH2 inflammation. Treatment of obese mice with a small molecule PPARg agonist prevented development of TH17 pathology in AD and unlocked robust therapeutic responsiveness to targeted anti-TH2 biologics. These studies reveal the effects of obesity on immunological disease and demonstrate a precision medicine approach to target the immune dysregulation caused by obesity to restore efficacy of a biological immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE189476 | GEO | 2022/03/29

REPOSITORIES: GEO

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Project description:The expression of adipogenic genes is decreased in obesity and diabetes mellitus ; Samuel T. Nadler*, Jonathan P. Stoehr*, Kathryn L. Schueler*, Gene Tanimoto, Brian S. Yandell, and Alan D. Attie*,Â§ ; Departments of * Biochemistry, and Statistics and Horticulture, University of Wisconsin, Madison, WI, 53706; and Affymetrix, Inc., Santa Clara, CA 95051 ; Communicated by Neal L. First, University of Wisconsin, Madison, WI, July 13, 2000 (received for review April 3, 2000) ; Obesity is strongly correlated with type 2 diabetes mellitus, a common disorder of glucose and lipid metabolism. Although adipocytes are critical in obesity, their role in diabetes has only recently been appreciated. We conducted studies by using DNA microarrays to identify differences in gene expression in adipose tissue from lean, obese, and obese-diabetic mice. The expression level of over 11,000 transcripts was analyzed, and 214 transcripts showed significant differences between lean and obese mice. Surprisingly, the expression of genes normally associated with adipocyte differentiation were down-regulated in obesity. Not all obese individuals will become diabetic; many remain normoglycemic despite profound obesity. Understanding the transition to obesity with concomitant diabetes will provide important clues to the pathogenesis of type 2 diabetes. Therefore, we examined the levels of gene expression in adipose tissue from five groups of obese mice with varying degrees of hyperglycemia, and we identified 88 genes whose expression strongly correlated with diabetes severity. This group included many genes that are known to be involved in signal transduction and energy metabolism as well as genes not previously examined in the context of diabetes. Our data show that a decrease in expression of genes normally involved in adipogenesis is associated with obesity, and we further identify genes important for subsequent development of type 2 diabetes mellitus. Experiment Overall Design: For obesity study, lean samples include C57BL/6J lean, (C57BL/6J X BTBR) F1 and BTBR lean, obese sampples incluse C57BL/6J-ob/ob, (C57BL/6J X BTBR) F2-ob/ob and BTBR-ob/ob. All samples are subjected to Mu11K A and B arrays. Experiment Overall Design: For diabetes study, B6-ob/ob, (C57BL/6J X BTBR) F2-ob/ob low glucose, (C57BL/6J X BTBR) F2-ob/ob medium glucose, (C57BL/6J X BTBR) F2-ob/ob high glucose, and BTBR-ob/ob samples were analyzed for genes whose expression levels changes correlated with the plasma glucose levels in these mice. All samples are subjected to Mu11K A and B arrays.

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Correcting altered immunological responses in obesity restores efficacy of targeted biologic therapy for inflammatory disease

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