PI3Kγ activity in leukocytes promotes adipose tissue inflammation and early-onset insulin resistance during obesity

Breasson, Ludovic; Becattini, Barbara; Sardi, Claudia; Molinaro, Angela; Zani, Fabio; Marone, Romina; Botindari, Fabrizio; Bousquenaud, Mélanie; Rüegg, Curzio; Wymann, Matthias P.; Solinas, Giovanni

doi:10.1126/scisignal.aaf2969

Cited by 34 publications

(54 citation statements)

References 42 publications

(70 reference statements)

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“…In vivo metabolic assays db/db C57BL/KSs mice were obtained from The Jackson Laboratory (Bar Harbor, ME, USA), and db/db-PI3Kg 2/2 mice were generated by backcrossing PI3Kg 2/2 mice from C57BL/6J (1,8) into the C57BL/KS genetic background for .10 generations. Experimental mice-10 db/db-PI3Kg 2/2 mice and 10 db/db control mice-were obtained from db/+ breeders and db/+-PI3Kg 2/2 mice in pure C57BL/KS background, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Obesity is the major risk factor that drives type 2 diabetes epidemics by promoting insulin resistance and loss of pancreatic b-cell mass and function. Preclinical studies show that the inhibition of class 1 PI3K reduces adiposity and improves blood glucose homeostasis in rodents and primates (1)(2)(3)(4)(5)(6)(7)(8). Thus, pharmacologic inhibition of specific class 1 PI3Ks may be an effective treatment for obesitydriven diabetes in humans.…”

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confidence: 99%

“…Class 1A PI3Ks are recruited to receptor tyrosine kinases via their p85-like regulatory subunits, which bind to tyrosine-phosphorylated proteins via their SH2 domains, whereas class 1B PI3Kg binds to p101 and p84 adapter subunits, which do not interact with tyrosinephosphorylated proteins and are recruited by activated GPCRs (9). PI3Kg activity is induced by potent metabolic signals, such as b-adrenergic receptors, and immune signals, including chemokine receptors and TLRs; thus, PI3Kg operates at the interface between metabolic homeostasis and immunity (8)(9)(10). Data from our laboratory and from another group have demonstrated that mice that lack PI3Kg are protected from diet-induced obesity and insulin resistance by mechanisms that involve increased energy expenditure and lipolysis and reduced adipose tissue inflammation (1,2,8).…”

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confidence: 99%

“…PI3Kg activity is induced by potent metabolic signals, such as b-adrenergic receptors, and immune signals, including chemokine receptors and TLRs; thus, PI3Kg operates at the interface between metabolic homeostasis and immunity (8)(9)(10). Data from our laboratory and from another group have demonstrated that mice that lack PI3Kg are protected from diet-induced obesity and insulin resistance by mechanisms that involve increased energy expenditure and lipolysis and reduced adipose tissue inflammation (1,2,8). These results were also confirmed and extended by another study that showed that pharmacologic inhibition of PI3Kg also reduced adiposity and increased lipolysis (5).…”

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confidence: 99%

“…Indeed, it has been reported that PI3Kg activity in pancreatic b cells plays a major role in sustaining insulin secretion by maintaining the ready releasable pool of insulin granules and by driving insulin secretion in response to glucose and glucosedependent insulinotropic polypeptide (11)(12)(13)(14). In mouse models of diet-induced obesity, PI3Kg ablation markedly improves adiposity, insulin sensitivity, and glucose homeostasis by a mechanism that is largely leptin dependent (1,2,8); however, it must be considered that these studies were performed in C57BL/6J mice, a genetic background that is prone to develop obesity-driven insulin resistance, but not overt b-cell dysfunction and diabetes. To investigate the effects of PI3Kg ablation in a genetic background that is prone to b-cell failure, we have generated and phenotyped mice with systemic PI3Kg ablation in db/db C57Bl/KS mice, a model for obesity-driven b-cell failure and type 2 diabetes.…”

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confidence: 99%

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PI3Kγ ablation does not promote diabetes indb/dbmice, but improves insulin sensitivity and reduces pancreatic β‐cell apoptosis

et al. 2017

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PI3Kγ has emerged as a promising target for the treatment of obesity and insulin resistance; however, previous studies have indicated that PI3Kγ activity in pancreatic β cells is required for normal insulin secretion in response to glucose. Hence, a possible deterioration of insulin secretion capacity in patients who are predisposed to the failure of pancreatic β-cell function is a major concern for the pharmacologic inhibition of PI3Kγ. To address this issue, we investigated the effects of PI3Kγ ablation in diabetic mice, a genetic model of obesity-driven β-cell failure and diabetes. Mice that lacked PI3Kγ were backcrossed into mice C57BL/KS (>10 generations) to obtain γ mice. γ mice and control mice were phenotyped for glucose homeostasis, insulin sensitivity, insulin secretion, steatosis, metabolic inflammation, pancreatic islet morphometry, islet cellular composition, and inflammation. Pancreatic β-cell apoptosis and proliferation were also evaluated.γ mice and control mice developed similar body weight, steatosis, glycemia, and insulin levels after a glucose load; however, γ mice displayed improved insulin tolerance, higher levels of fasting serum insulin, and lower pancreatic insulin content. In γ mice, the number of adipose tissue macrophages was similar to control, but displayed reduced adipose tissue neutrophils and M2-polarized adipose tissue gene expression. Finally, γ mice have more pancreatic β cells and larger islets than mice, despite displaying similar islet inflammation. This phenotype could be explained by reduced β-cell apoptosis inγ mice compared with control mice. Our results are consistent with the concept that the beneficial action of PI3Kγ ablation in obesity-driven glucose intolerance is largely a result of its leptin-dependent effects on adiposity and, to a lesser extent, the promotion of adipose tissue neutrophil recruitment and M1 polarization of gene expression. Of importance, our data challenge the concept that PI3Kγ is required for insulin secretion in response to glucose, and indicate that PI3Kγ ablation protects mice from β-cell apoptosis and improves fasting insulin levels. We conclude that PI3Kγ inhibition in obese patients who are predisposed to β-cell failure is not expected to produce adverse effects on insulin secretion.-Breasson, L., Sardi, C., Becattini, B., Zani, F., Solinas, G. PI3Kγ ablation does not promote diabetes in mice, but improves insulin sensitivity and reduces pancreatic β-cell apoptosis.

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Section: Methodsmentioning

confidence: 99%