Journal
DIABETES
Volume 67, Issue 5, Pages 841-848Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db17-0788
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Funding
- American Heart Association [16POST31350039]
- National Natural Science Foundation of China [81600610]
- Noland Scholarship from the California Institute of Technology
- Department of Veterans Affairs (VA Merit Review) [I01BX002709, I01BX000323]
- S.K.M.'s personal fund
- NATIONAL INSTITUTE ON DRUG ABUSE [R29DA011311] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX003934, I01BX002709] Funding Source: NIH RePORTER
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The activation of Kupffer cells (KCs) and monocyte-derived recruited macrophages (McM Phi s) in the liver contributes to obesity-induced insulin resistance and type 2 diabetes. Mice with diet-induced obesity (DIO mice) treated with chromogranin A peptide catestatin (CST) showed several positive results. These included decreased hepatic/plasma lipids and plasma insulin, diminished expression of gluconeogenic genes, attenuated expression of proinflammatory genes, increased expression of anti-inflammatory genes in McM Phi s, and inhibition of the infiltration of McM Phi s resulting in improvement of insulin sensitivity. Systemic CST knockout (CST-KO) mice on normal chow diet (NCD) ate more food, gained weight, and displayed elevated blood glucose and insulin levels. Supplementation of CST normalized glucose and insulin levels. To verify that the CST deficiency caused macrophages to be very proinflammatory in CST-KO NCD mice and produced glucose intolerance, we tested the effects of (sorted with FACS) F4/80(+)Ly6C(-) cells (representing KCs) and F4/80(-)Ly6C(+) cells (representing McM Phi s) on hepatic glucose production (HGP). Both basal HGP and glucagon-induced HGP were markedly increased in hepatocytes cocultured with KCs and McM Phi s from NCD-fed CST-KO mice, and the effect was abrogated upon pretreatment of CST-KO macrophages with CST. Thus, we provide a novel mechanism of HGP suppression through CST-mediated inhibition of macrophage infiltration and function.
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