Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

HSP72 prevents peripheral tissue lipotoxicity and preserves insulin sensitivity by increasing oxidative metabolism in skeletal muscle (#162)

Darren Henstridge 1 , Clinton Bruce 1 2 3 , Brian Drew 1 4 , Emma Estevez 1 , Nadine Watson 1 , Jason Chung 1 , Robert Lee-Young 1 , Tim Connor 2 , Matthew Watt 3 , Hong-wei Qian 1 , Paul Gregorevic 1 , Kevin Carpenter 5 , Mark Hargreaves 6 , Sean McGee 2 , Andrea Hevener 4 , Mark Febbraio 1
  1. Baker IDI Heart & Diabetes Institute, Melbourne, VIC, Australia
  2. Deakin Univrsity, Melbourne
  3. Monash University, Melbourne
  4. University of Califronia, Los Angeles
  5. The University of Sydney, Sydney
  6. Melbourne University, Melbourne

We have previously shown that induction of heat shock protein 72 (HSP72) in skeletal muscle (SkM) protects against obesity-induced insulin resistance, but the mechanisms underlying this are unclear (Chung et al. PNAS, 2008). Here we show that HSP72 over-expression plays a role in SkM oxidative capacity. SkM-specific transgenic HSP72 (HSP72Tg) and control (WT) mice were fed a regular chow (chow) or high fat diet (HFD) for 10 weeks. Although the HFD markedly increased weight, intramuscular lipid accumulation (DAGs and TAGs) and insulin resistance in WT mice, these diet-induced alterations were prevented in HSP72Tg animals. Whole body oxygen consumption, physical activity, fatty acid oxidation, SkM oxidative enzyme activity and exercise endurance capacity were increased (P<0.05) in HSP72Tg mice irrespective of diet. Consistent with an enhanced oxidative metabolism phenotype, HSP72Tg mice exhibited an increase in mitochondria number and Tfam mRNA expression (P<0.05). These changes were associated with an increase in the phosphorylation of AMPK, AMPK activity levels, SIRT1 protein expression and lipoprotein lipase levels in the HSP72Tg mice (P<0.05). Some markers of autophagy and mitophagy were altered in the SkM of HSP72Tg mice but did not fit with any traditional pro or anti autophagy/mitophagy paradigm. Further, improvements in organs other than SkM were observed such as a decrease in hepatic steatosis with HFD, even though the transgene was not expressed in the liver. To determine whether an increase in physical activity was driving the phenotype in the transgenic mice, we generated a HSP72 adeno-associated virus and overexpressed HSP72 in one tibialis anterior muscle. In this model, HSP72 overexpression was still able to improve HFD induced defects in SkM glucose clearance. Together, these data indicate that HSP72 prevents obesity and insulin resistance by increasing oxidative metabolism in SkM which protects peripheral tissues from the deleterious effects of a HFD.