8,9]. Recent investigations indicated that the inflammatory and stress responses pathways are highly integrated and they work most-likely in vicious cycles, which largely explain the myriad of disorders associated with obesity [6,10,11]. The perturbation of the inflammatory and stress responses is known to activate several stress kinases but the best characterized are the c-Jun NH2 terminal kinase (JNK) and the inhibitor of kB kinase-b (IKKb), both of them canphosphorylate the insulin receptor substrate-1 (IRS-1) and rendering this crucial intermediate a poor substrate for the activated insulin receptor [12,13,14,15,16]. Heat shock response (HSR); a crucial host-defense system against various pathological, physiological and environmental stressors, is one of the key pathways that was shown to be impaired in obesity-induced insulin resistance. HSR involves the immediate activation of a set of highly conserved heat shock proteins (HSPs) referred to as molecular chaperones and their master regulators; the heat shock transcription factors (HSFs) [17,18,19]. To maintain normal protein homeostasis (proteostasis), HSPs act with other components of the proteostasis network as a sensor to detect misfolded and aggregated proteins and through non-covalent interactions, they assist in their proper folding or targeting them to degradation through the ubiquitindependent proteasome and lysosome-mediated autophagy [19,20,21,22]. In addition to their chaperone activity, certain HSPs have the ability to mitigate damages resulting from metabolic disorders by physically interacting with key stress and apoptotic enzymes and suppressing the inflammatory response, alleviating various forms of metabolic stress and promoting cellPLOS ONE | www.plosone.orgDownregulation of DNAJB3 in Obese Humanssurvival by blocking caspase-dependent apoptosis [20,23]. HSPs can also be released into the circulation, but in contrast to their intracellular roles, extracellular HSPs exert an immune-stimulatory effect by interacting with pattern recognition receptors, such as toll-like receptors, and thereby activate the host inflammatory response [24,25].L-Phenylalanine HSPs are broadly classified, on the basis of their apparent molecular weight, amino acid sequences and functions into distinct families.Bergamottin In mammalian cells, six major families of HSPs with distinct functional classes have been described to date and they consist of HSP-110/HSPH, HSP-90/HSPC, HSP70/HSPA, HSP-60/HSPD, HSP-40/DNAJ and the small HSPs/HSPB [26,27].PMID:23892407 Some members of these families are ubiquitously expressed, whereas others are expressed in response to a wide variety of stress conditions and thus, highlighting their critical role in maintaining cellular homeostasis and tissue integrity [28]. The status of the HSR and its role in the pathophysiology of obesity and its complications began to be unraveled. Recent studies suggested that HSR is impaired in obesity-induced insulin resistance both in humans and experimental animal models [29,30,31]. The initial studies were carried out on muscle biopsies from type 2 diabetic (T2D) patients and they showed a reduction of HSP-72 expression that correlated with the degree of insulin resistance [8,9]. These observations were further supported in experimental animal models demonstrating impaired expression of HSP-72 in the rat model of streptozotocininduced diabetes [32] and reduced expression of both HSP-25 and HSP-72 in the insulin-resistant aged rats [52,53]. Consistent with these f.