PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance

Abstract

Obesity is associated with a chronic low-grade inflammation, and specific antiinflammatory interventions may be beneficial for the treatment of type 2 diabetes and other obesity-related diseases. The lipid kinase PI3Kγ is a central proinflammatory signal transducer that plays a major role in leukocyte chemotaxis, mast cell degranulation, and endothelial cell activation. It was also reported that PI3Kγ activity within hematopoietic cells plays an important role in obesity-induced inflammation and insulin resistance. Here, we show that protection from insulin resistance, metabolic inflammation, and fatty liver in mice lacking functional PI3Kγ is largely consequent to their leaner phenotype. We also show that this phenotype is largely based on decreased fat gain, despite normal caloric intake, consequent to increased energy expenditure. Furthermore, our data show that PI3Kγ action on diet-induced obesity depends on PI3Kγ activity within a nonhematopoietic compartment, where it promotes energetic efficiency for fat mass gain. We also show that metabolic modulation by PI3Kγ depends on its lipid kinase activity and might involve kinase-independent signaling. Thus, PI3Kγ is an unexpected but promising drug target for the treatment of obesity and its complications.energy balance | ectopic lipids | metabolic stress O besity is characterized by a chronic low-grade inflammation (1-5), and clinical studies suggest that antiinflammatory treatments may improve glucose homeostasis in diabetics (6-9). Thus, the identification of the molecular links between inflammation and metabolic homeostasis is fundamental to a better understanding of the pathophysiology of type 2 diabetes and other obesity-related diseases. Here, we have investigated the role of the lipid kinase PI3Kγ in diet-induced obesity, metabolic inflammation, and insulin resistance. PI3Kγ is the only class IB member of the PI3K family, and unlike the class IA PI3Ks (PI3Kα, PI3Kβ, and PI3Kδ), it was not implicated in insulin or insulin-like growth factor 1 (IGF-1) signaling (10-13). PI3Kγ is selectively recruited to G protein-coupled receptors implicated in inflammation and metabolic homeostasis, including chemokine receptors, β-adrenergic signaling, and angiotensin II receptors (13-17). On activation, PI3Kγ controls two major second messengers: phosphatidylinositol(3,4,5)-tris-phosphate (PIP 3 ) through direct phosphorylation of phosphatidylinositol 4,5 bisphosphate and cAMP by a kinase-independent mechanism (18). PI3Kγ is most abundant in cells of hematopoietic origin, but it is also expressed, at a much lower level, in a variety of nonhematopoietic cell types (19). Previous studies proposed a role for PI3Kγ in the control of insulin secretion, thereby suggesting that loss of PI3Kγ may predispose to glucose intolerance (20)(21)(22). By contrast, the results presented in this manuscript together with a recent study (23) show that mice lacking PI3Kγ are dramatically protected from diet-induced obesity and glucose intolerance. Kobayashi et al. (23) concluded that the ...

PI3K signaling in the pathogenesis of obesity: The cause and the cure

“…Given their expression pattern limited to immune cells, p110δ and p110γ have been initially studied preferentially in models of acute and chronic inflammatory diseases, as they have been found M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 7 "partners in crime" in these pathologies (Rommel, Camps, 2007). Nonetheless, recent studies indicate a complex pattern of expression of p110γ, that includes the presence of small amount of the this enzyme in tissues other than immune cells, such as heart, adipose tissue and brain (Becattini et al , 2011, Ghigo et al , 2012, Patrucco et al , 2004, Schmidt et al , 2013.…”

Scaffolding Function of PI3Kgamma Emerges from Enzyme's Shadow

“…The regulation of cAMP by kinase-independent mechanism of PI3Kγ in the cardiomyocytes is also implicated in diet-induced thermogenesis. It has been shown that the kinase-independent pathway of PI3Kγ is a negative regulator of PKA-mediated hormone sensitive lipase activation in white adipose tissue[57]. …”

Differences in Body Temperature Variability Between Subjects With and Without Diabetes and Predictive Value for Cardiovascular Events

“…15, 16 In addition, there has recently been reported to be a close link between the pathogenesis of diabetes and thermoregulation. 17, 18 The difference of interaction between vascular function and thermoregulation between diabetes and nondiabetes, however, had not been elucidated concisely.…”