The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance

The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2ΔLysM), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2ΔLysM and Ucp2fl/fl mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/fl littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance.

Download Full-text

Adipose tissue inflammation and metabolic dysfunction: a clinical perspective

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2013-0032 ◽

2013 ◽

Vol 15 (1) ◽

Cited By ~ 2

Author(s):

Charmaine S. Tam ◽

Leanne M. Redman

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Low Grade ◽

Metabolic Dysfunction ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Proinflammatory Mediators ◽

Low Grade Inflammation

AbstractObesity is characterized by a state of chronic low-grade inflammation due to increased immune cells, specifically infiltrated macrophages into adipose tissue, which in turn secrete a range of proinflammatory mediators. This nonselective low-grade inflammation of adipose tissue is systemic in nature and can impair insulin signaling pathways, thus, increasing the risk of developing insulin resistance and type 2 diabetes. The aim of this review is to provide an update on clinical studies examining the role of adipose tissue in the development of obesity-associated complications in humans. We will discuss adipose tissue inflammation during different scenarios of energy imbalance and metabolic dysfunction including obesity and overfeeding, weight loss by calorie restriction or bariatric surgery, and conditions of insulin resistance (diabetes, polycystic ovarian syndrome).

Download Full-text

CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00344.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. E309-E325 ◽

Cited By ~ 18

Author(s):

Pia S. Petersen ◽

Xia Lei ◽

Risa M. Wolf ◽

Susana Rodriguez ◽

Stefanie Y. Tan ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Glucose Metabolism ◽

Resistance Index ◽

Activity Level ◽

Low Grade ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Metabolic Role ◽

Obesity And Diabetes

Chronic low-grade inflammation and cellular stress are important contributors to obesity-linked metabolic dysfunction. Here, we uncover an immune-metabolic role for C1q/TNF-related protein 7 (CTRP7), a secretory protein of the C1q family with previously unknown function. In obese humans, circulating CTRP7 levels were markedly elevated and positively correlated with body mass index, glucose, insulin, insulin resistance index, hemoglobin A1c, and triglyceride levels. Expression of CTRP7 in liver was also significantly upregulated in obese humans and positively correlated with gluconeogenic genes. In mice, Ctrp7 expression was differentially modulated in various tissues by fasting and refeeding and by diet-induced obesity. A genetic loss-of-function mouse model was used to determine the requirement of CTRP7 for metabolic homeostasis. When fed a control low-fat diet, male or female mice lacking CTRP7 were indistinguishable from wild-type littermates. In obese male mice consuming a high-fat diet, however, CTRP7 deficiency attenuated insulin resistance and enhanced glucose tolerance, effects that were independent of body weight, metabolic rate, and physical activity level. Improved glucose metabolism in CTRP7-deficient mice was associated with reduced adipose tissue inflammation, as well as decreased liver fibrosis and cellular oxidative and endoplasmic reticulum stress. These results provide a link between elevated CTRP7 levels and impaired glucose metabolism, frequently associated with obesity. Inhibiting CTRP7 action may confer beneficial metabolic outcomes in the setting of obesity and diabetes.

Download Full-text

Role of brown adipose tissue in modulating adipose tissue inflammation and insulin resistance in high-fat diet fed mice

European Journal of Pharmacology ◽

10.1016/j.ejphar.2019.02.044 ◽

2019 ◽

Vol 854 ◽

pp. 354-364 ◽

Cited By ~ 7

Author(s):

Kripa Shankar ◽

Durgesh Kumar ◽

Sanchita Gupta ◽

Salil Varshney ◽

Sujith Rajan ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

High Fat Diet ◽

Adipose Tissue Inflammation ◽

High Fat ◽

Tissue Inflammation ◽

Brown Adipose

Download Full-text

A2B Adenosine Receptors Prevent Insulin Resistance by Inhibiting Adipose Tissue Inflammation via Maintaining Alternative Macrophage Activation

Diabetes ◽

10.2337/db13-0573 ◽

2013 ◽

Vol 63 (3) ◽

pp. 850-866 ◽

Cited By ~ 62

Author(s):

B. Csoka ◽

B. Koscso ◽

G. Toro ◽

E. Kokai ◽

L. Virag ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Adenosine Receptors ◽

Macrophage Activation ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation

Download Full-text

Abstract 3592: Early Detection Of CD4-positive Lymphocytes In Adipose Tissue During The Development Of Insulin Resistance

Circulation ◽

10.1161/circ.116.suppl_16.ii_813-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Katharina Hess ◽

Nikolaus Marx ◽

Martin Wabitsch ◽

Thomas Skurk ◽

Hans Hauner ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Immunohistochemical Staining ◽

Human Adipose Tissue ◽

Adipose Tissue Inflammation ◽

Rt Pcr ◽

Tissue Inflammation ◽

Visceral Adipose

Background: Adipose tissue inflammation may play a critical role in the pathogenesis of insulin resistance (IR) and arteriosclerosis. Previous work has mainly focused on the role of macrophages in human adipose tissue, but little is known about pro-inflammatory T-lymphocytes. Therefore the present study examined the role of CD4-positive lymphocytes in adipose tissue inflammation and IR. Results: Both, CD4-positive lymphocytes and macrophages are present in human visceral adipose tissue as determined by immunohistochemical staining. Most macrophages were HLA-DR positive, reflecting activation through IFNγ, a cytokine released from CD4-positive lymphocytes. Furthermore, SDF-1α, a T-cell chemotactic protein, was also detectable in human adipose tissue. RT-PCR analyses confirmed the expression of IFNγ and SDF1α in visceral adipose tissue. Freshly isolated human adipocytes as well SGBS adipocyte cells express SDF-1α with a down regulation of its expression during adipocyte differentiation in both cell types. In a mouse model of IR, high fat diet induced IR already after 5 weeks which was associated with a marked lymphocyte infiltration in visceral adipose tissue as determined by immunohistochemical staining and RT-PCR. In contrast, macrophages were absent after 5 weeks of diet but could be detected at week 10, suggesting early infiltration of lymphocytes during the development of IR. Conclusion: Pro-inflammatory T-lymphocytes are present in visceral adipose tissue and may contribute to local inflammatory cell activation before the appearance of macrophages. These data suggest that lymphocytes may play an important role in the initiation and perpetuation of adipose tissue inflammation as well as the development of insulin resistance.

Download Full-text