Hematopoietic AMPK β1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity

Abstract

Individuals who are obese are frequently insulin resistant, putting them at increased risk of developing type 2 diabetes and its associated adverse health conditions. The accumulation in adipose tissue of macrophages in an inflammatory state is a hallmark of obesity-induced insulin resistance. Here, we reveal a role for AMPK β1 in protecting macrophages from inflammation under high lipid exposure. Genetic deletion of the AMPK β1 subunit in mice (referred to herein as β1 -/-mice) reduced macrophage AMPK activity, acetyl-CoA carboxylase phosphorylation, and mitochondrial content, resulting in reduced rates of fatty acid oxidation. β1 -/-macrophages displayed increased levels of diacylglycerol and markers of inflammation, effects that were reproduced in WT macrophages by inhibiting fatty acid oxidation and, conversely, prevented by pharmacological activation of AMPK β1-containing complexes. The effect of AMPK β1 loss in macrophages was tested in vivo by transplantation of bone marrow from WT or β1 -/-mice into WT recipients. When challenged with a high-fat diet, mice that received β1 -/-bone marrow displayed enhanced adipose tissue macrophage inflammation and liver insulin resistance compared with animals that received WT bone marrow. Thus, activation of AMPK β1 and increasing fatty acid oxidation in macrophages may represent a new therapeutic approach for the treatment of insulin resistance.

Luteolin reduces obesity-associated insulin resistance in mice by activating AMPKα1 signalling in adipose tissue macrophages

“…AMPKα1 plays an important role in the suppression of proinflammatory responses and macrophage inflammatory polarisation [21,22]. Accompanied by improvements in insulin resistance and ATM inflammation, mice in the HFD + LU10 and HFD + LU20 groups also showed increased EAT AMPKα1 signalling (Fig.…”

“…The catalytic subunit AMPKα1 is mainly expressed in macrophages and suppresses associated proinflammatory responses and polarisation [21,22]. Previous studies have reported that LU can enhance the phosphorylation of AMPK in HepG2 cells [23] and 3T3-L1 adipocytes [24].…”

AMP-activated Protein Kinase Suppresses Arachidonate 15-Lipoxygenase Expression in Interleukin 4-polarized Human Macrophages

“…A number of previous studies have reported the anti-inflammatory phenotype of AMPK-activated macrophages (18,29,30) with the notion that IL-4-induced polarization is attenuated in AMPK␣1-deficient murine macrophages (19). In human macrophages, AMPK activation does not generally seem to affect IL-4-induced gene expression.…”

AMPK β1 reduces tumor progression and improves survival in p53 null mice

“…For mRNA analysis, tissues were lysed in TRIzol reagent (Life Technologies) and RNA was extracted for qRT‐PCR and mRNA assessed as described (Galic et al ., 2011). …”

“…The AMPK β1 isoform plays a vital role in regulating AMPK heterotrimer formation and enzyme activity in mouse liver and hematological cells such as macrophages and T cells where it increases fatty acid oxidation, suppresses fatty acid synthesis, and inhibits inflammatory pathways (Blagih et al ., 2015; Dzamko et al ., 2010; Fullerton et al ., 2015; Galic et al ., 2011). It is also the primary subunit which is targeted by small‐molecule direct AMPK activators such as A769662 (Cool et al ., 2006; Sanders et al ., 2007; Scott et al ., 2014), MT‐63‐78 (Zadra et al ., 2014), and salicylate (Hawley et al ., 2012), all of which have been shown to reduce cancer cell proliferation in some (Huang et al ., 2008; O'Brien et al ., 2015; Zadra et al ., 2014), but not all studies (Vincent et al ., 2015).…”