During obesity, macrophages can infiltrate metabolic tissues, and contribute to chronic low-grade inflammation, and mediate insulin resistance and diabetes. Recent studies have elucidated the metabolic role of JAK2, a key mediator downstream of various cytokines and growth factors. Our study addresses the essential role of macrophage JAK2 in the pathogenesis to obesity-associated inflammation and insulin resistance. During high-fat diet (HFD) feeding, macrophage-specific JAK2 knockout (M-JAK2-/-) mice gained less body weight compared to wildtype littermate control (M-JAK2+/+) mice and were protected from HFD-induced systemic insulin resistance. Histological analysis revealed smaller adipocytes and qPCR analysis showed upregulated expression of some adipogenesis markers in visceral adipose tissue (VAT) of HFD-fed M-JAK2-/- mice. There were decreased crown-like structures in VAT along with reduced mRNA expression of some macrophage markers and chemokines in liver and VAT of HFD-fed M-JAK2-/- mice. Peritoneal macrophages from M-JAK2-/- mice and Jak2 knockdown in macrophage cell line RAW 264.7 also showed lower levels of chemokine expression and reduced phosphorylated STAT3. However, leptin-dependent effects on augmenting chemokine expression in RAW 264.7 cells did not require JAK2. Collectively, our findings show that macrophage JAK2 deficiency improves systemic insulin sensitivity and reduces inflammation in VAT and liver in response to metabolic stress.
Bibliographical noteFunding Information:
We would like to thank Dr. Tianru Jin, University Health Network, Toronto, ON, USA, for generously providing the RAW 264.7 cells. We would like to thank Dr. Jenny Jongstra-Bilen, Dr. Sally Shi and Jara Brunt for their technical advice with the experiments. This work was supported by Canadian Institute of Health Research (CIHR) operating grant MOP-142193. M.W. is supported by the Canada Research Chair in Signal Transduction in Diabetes Pathogenesis. D.A.W is funded by the CIHR (FDN-148385). H.R.D received a CIHR Canadian Graduate Scholarship-Master's program award, a QEII-GSST award and a BBDC - UHN Graduate Award. T.S. is supported by a CIHR Doctoral Research Award, a CDA Doctoral Student Research Award and a Canadian Liver Foundation Graduate Studentship. X.S.R. is the recipient of a CDA Postdoctoral Fellowship Award. C.T.L. is a recipient of the Eliot Phillipson Clinician Scientist Training Program, a CDA Postdoctoral Fellowship, a CSEM Dr. Fernand Labrie Fellowship Research Award and a BBDC Postdoctoral Fellowship.