TY - JOUR
T1 - Suppressing adipocyte inflammation promotes insulin resistance in mice
AU - Zhu, Qingzhang
AU - An, Yu A.
AU - Kim, Min
AU - Zhang, Zhuzhen
AU - Zhao, Shangang
AU - Zhu, Yi
AU - Asterholm, Ingrid Wernstedt
AU - Kusminski, Christine M.
AU - Scherer, Philipp E.
N1 - Funding Information:
We thank all of the members of Scherer Laboratory for supporting this study. We also thank the UTSW Metabolic Core Facility, the Histopathology Core, UTSW ARC, Charlotte Lee for help with histology, and Bo Shan for assistance with BMDM isolation. This study was supported by US National Institutes of Health grants RC2-DK118620 , R01-DK55758 , R01-DK099110 , P01-DK088761 , and P01-AG051459 to PES. PES was also supported by an unrestricted research grant from the Novo Nordisk Foundation . IWA was supported by the Swedish Research Council , the Novo Nordisk Foundation and the Swedish Diabetes Foundation .
Funding Information:
We thank all of the members of Scherer Laboratory for supporting this study. We also thank the UTSW Metabolic Core Facility, the Histopathology Core, UTSW ARC, Charlotte Lee for help with histology, and Bo Shan for assistance with BMDM isolation. This study was supported by US National Institutes of Health grants RC2-DK118620, R01-DK55758, R01-DK099110, P01-DK088761, and P01-AG051459 to PES. PES was also supported by an unrestricted research grant from the Novo Nordisk Foundation. IWA was supported by the Swedish Research Council, the Novo Nordisk Foundation and the Swedish Diabetes Foundation.
Publisher Copyright:
© 2020 The Authors
PY - 2020/9
Y1 - 2020/9
N2 - Objective: Obesity-induced insulin resistance is closely associated with chronic subclinical inflammation in white adipose tissue. However, the mechanistic involvement of adipocyte-derived inflammation under these disease conditions remains unclear. Our aim was to investigate the relative inflammation-related contributions of adipocytes and macrophages to insulin sensitivity. Methods: RIDα/β is an adenoviral protein complex that inhibits several inflammatory pathways, including TLR4, TNFα, and IL1β signaling. We generated novel mouse models with adipocyte-specific and macrophage-specific doxycycline (dox)-inducible RIDα/β-transgenic mice (RIDad and RIDmac mice, respectively). Results: RIDα/β induction significantly reduced LPS-stimulated inflammatory markers, such as Tnf, Il1b, and Saa3 in adipose tissues. Surprisingly, RIDad mice had elevated levels of postprandial glucose and insulin and exhibited glucose intolerance and insulin resistance, even under chow-fed conditions. Moreover, the RIDad mice displayed further insulin resistance under obesogenic (high-fat diet, HFD) conditions despite reduced weight gain. In addition, under pre-existing obese and inflamed conditions on an HFD, subsequent induction of RIDα/β in RIDad mice reduced body weight gain, further exacerbating glucose tolerance, enhancing insulin resistance and fatty liver, and reducing adiponectin levels. This occurred despite effective suppression of the inflammatory pathways (including TNFα and IL1β). In contrast, RIDmac mice, upon HFD feeding, displayed similar weight gain, comparable adiponectin levels, and insulin sensitivity, suggesting that the inflammatory properties of macrophages did not exert a negative impact on metabolic readouts. RIDα/β expression and the ensuing suppression of inflammation in adipocytes enhanced adipose tissue fibrosis and reduced vascularization. Conclusion: Our novel findings further corroborate our previous observations suggesting that suppressing adipocyte inflammation impairs adipose tissue function and promotes insulin resistance, despite beneficial effects on weight gain.
AB - Objective: Obesity-induced insulin resistance is closely associated with chronic subclinical inflammation in white adipose tissue. However, the mechanistic involvement of adipocyte-derived inflammation under these disease conditions remains unclear. Our aim was to investigate the relative inflammation-related contributions of adipocytes and macrophages to insulin sensitivity. Methods: RIDα/β is an adenoviral protein complex that inhibits several inflammatory pathways, including TLR4, TNFα, and IL1β signaling. We generated novel mouse models with adipocyte-specific and macrophage-specific doxycycline (dox)-inducible RIDα/β-transgenic mice (RIDad and RIDmac mice, respectively). Results: RIDα/β induction significantly reduced LPS-stimulated inflammatory markers, such as Tnf, Il1b, and Saa3 in adipose tissues. Surprisingly, RIDad mice had elevated levels of postprandial glucose and insulin and exhibited glucose intolerance and insulin resistance, even under chow-fed conditions. Moreover, the RIDad mice displayed further insulin resistance under obesogenic (high-fat diet, HFD) conditions despite reduced weight gain. In addition, under pre-existing obese and inflamed conditions on an HFD, subsequent induction of RIDα/β in RIDad mice reduced body weight gain, further exacerbating glucose tolerance, enhancing insulin resistance and fatty liver, and reducing adiponectin levels. This occurred despite effective suppression of the inflammatory pathways (including TNFα and IL1β). In contrast, RIDmac mice, upon HFD feeding, displayed similar weight gain, comparable adiponectin levels, and insulin sensitivity, suggesting that the inflammatory properties of macrophages did not exert a negative impact on metabolic readouts. RIDα/β expression and the ensuing suppression of inflammation in adipocytes enhanced adipose tissue fibrosis and reduced vascularization. Conclusion: Our novel findings further corroborate our previous observations suggesting that suppressing adipocyte inflammation impairs adipose tissue function and promotes insulin resistance, despite beneficial effects on weight gain.
KW - Adipocyte
KW - Inflammation
KW - Insulin resistance
UR - http://www.scopus.com/inward/record.url?scp=85085645491&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085645491&partnerID=8YFLogxK
U2 - 10.1016/j.molmet.2020.101010
DO - 10.1016/j.molmet.2020.101010
M3 - Article
C2 - 32408016
AN - SCOPUS:85085645491
SN - 2212-8778
VL - 39
JO - Molecular Metabolism
JF - Molecular Metabolism
M1 - 101010
ER -