Adipose specific C-C motif chemokine ligand (CCL) 19 overexpression drives the mice to both insulin resistance and weight gain.

Abstract: ObjectivesThe pathophysiological features of overweight and/or obesity are adipose tissue inflammation and infiltration of activated immune cells, such as macrophages. This results in the increased production of adipokines secreted by adipocytes, as well as additional inflammatory cytokines and chemokines. We previously reported that co-culture of adipocytes and endotoxin-stimulated macrophages significantly increases the expression of C-C motif ligand 19 (CCL19), suggesting that periodontal bacteria-activated circulating monocytic cells may further enhance adipose tissue inflammation upon migration into adipose tissue via its receptor, C-C chemokine receptor type 7 (CCR7). Here, we investigated the effects of CCL19/CCR7 pathway on subsequent metabolic disorders potentially enhanced by periodontal inflammation.MethodsAdipocyte-specific Ccl19 knock-in (KI) mice were generated, and the mice were fed either a normal diet or 40% or 60% fat-diet (FD) to investigate the effects of CCL19 on the induction of inflammation and lipid metabolism.ResultsCcl19 KI mice exhibited increased inflammatory signs in the adipose tissues and enlarged subcutaneous white and brown adipose tissue as compared with wild-type (WT) mice. Ccl19 KI mice were characterized by increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and decreased AMP-activated protein kinase α (AMPKα) phosphorylation in the adipose tissue. Peroxisome proliferators-activated receptor γ coactivator 1α (PGC1α) and uncoupling protein 1 (UCP1) protein expression was significantly reduced in brown adipose tissue of Ccl19 KI mice compared to that in WT mice. These changes were most marked when KI mice were fed a 40% FD, which resembled western style diet. ConclusionsActivation of CCL19/CCR7 pathway in adipose tissue inhibited AMPKα through activating ERK1/2, resulting in impaired lipid metabolism and energy regulation. Thus, subjects preferring western style diet, when accompanied by severe periodontal disease, may suffer from resistance to diet.