PI3Kα inhibition reduces obesity in mice

Lopez-Guadamillas, Elena; Muñoz-Martin, Maribel; Martinez, Sonia; Pastor, Joaquín; Fernandez-Marcos, Pablo J.; Serrano, Manuel

doi:10.18632/aging.101075

Cited by 21 publications

(26 citation statements)

References 21 publications

(26 reference statements)

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“…As discussed in our respective article, there are numerous reports in the literature demonstrating a profound lack of tissue specificity for the aP2-Cre strain, which complicates interpretation of phenotypes. Importantly, the phenotypes described in our previous and present work are consistent with those reported for long term pharmacological inhibition of p110α 20,21 , which adds additional weight to the validity of our findings.…”

Section: Discussionsupporting

confidence: 90%

“…Furthermore, adipose tissue-specific inactivation of p110α resulted in leaner mice due to increased energy expenditure 19 . Importantly, long-term pharmacological inhibition of p110α has previously been shown to protect mice and rhesus monkeys from diet-induced obesity, highlighting both the utility of PI3K inhibitors in metabolic studies and their therapeutic potential 20,21 . Although a worm ortholog of class I PI3K was the first gene ever reported to affect the rate of ageing 22 , the specific roles of PI3K in the context of processes associated with ageing have barely been investigated.…”

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confidence: 99%

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Increased mitochondrial and lipid metabolism is a conserved effect of Insulin/PI3K pathway downregulation in adipose tissue

Bettedi

Yan

Schuster

et al. 2020

Sci Rep

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The Insulin/IGF-1 signalling (IIS) pathway plays an essential role in the regulation of glucose and lipid homeostasis. At the same time, a reduction in the IIS pathway activity can extend lifespan and healthspan in various model organisms. Amongst a number of body organs that sense and respond to insulin/IGF-1, the adipose tissue has a central role in both the metabolic and lifespan effects of IIS at the organismal level. Genetic inactivation of IIS components specifically in the adipose tissue has been shown before to improve metabolic profile and extend lifespan in various model organisms. We sought to identify conserved molecular mechanisms that may underlie the beneficial effects of IIS inhibition in the adipose tissue, specifically at the level of phosphoinositide 3-kinase (PI3K), a key IIS effector molecule. To this end, we inactivated PI3K by genetic means in the fly fat body and by pharmacological inhibition in mammalian adipocytes. Gene expression studies revealed changes to metabolism and upregulation of mitochondrial activity in mouse adipocytes and fly fat bodies with downregulated PI3K, which were confirmed by biochemical assays in mammalian adipocytes. These data suggest that PI3K inactivation has a conserved effect of upregulating mitochondrial metabolism in both fly and mammalian adipose tissue, which likely contributes to the health-and lifespan extending effect of IIS pathway downregulation.

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Section: Discussionsupporting

confidence: 90%

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confidence: 99%

Increased mitochondrial and lipid metabolism is a conserved effect of Insulin/PI3K pathway downregulation in adipose tissue

Bettedi

Yan

Schuster

et al. 2020

Sci Rep

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“…Often components of this and related phospholipid signaling pathways are tumor suppressors [ 124 , 125 ]. Multiple components of the PI3K/PTEN/AKT/mTORC1 pathway have and are being considered for potential targeting in human cancer, e.g., p70S6K in breast cancer [ 126 ], as well as, obesity [ 127 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells

Abrams

Ruvolo

et al. 2017

Oncotarget

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A critical problem in leukemia as well as other cancer therapies is the development of chemotherapeutic drug-resistance. We have developed models of hematopoietic drug resistance that are based on expression of dominant-negative TP53 [TP53 (DN)] or constitutively-active MEK1 [MEK1(CA)] oncogenes in the presence of chemotherapeutic drugs. In human cancer, functional TP53 activity is often lost in human cancers. Also, activation of the Raf/MEK/ERK pathway frequently occurs due to mutations/amplification of upstream components of this and other interacting pathways. FL5.12 is an interleukin-3 (IL−3) dependent hematopoietic cell line that is sensitive to doxorubicin (a.k.a Adriamycin). FL/Doxo is a derivative cell line that was isolated by culturing the parental FL5.12 cells in doxorubicin for prolonged periods of time. FL/Doxo + TP53 (DN) and FL/Doxo + MEK1 (CA) are FL/Doxo derivate cell lines that were infected with retrovirus encoding TP53 (DN) or MEK1 (CA) and are more resistant to doxorubicin than FL/Doxo cells. This panel of cell lines displayed differences in the sensitivity to inhibitors that suppress mTORC1, BCL2/BCLXL, MEK1 or MDM2 activities, as well as, the proteasomal inhibitor MG132. The expression of key genes involved in cell growth and drug-resistance (e.g., MDM2, MDR1, BAX) also varied in these cells. Thus, we can begin to understand some of the key genes that are involved in the resistance of hematopoietic cells to chemotherapeutic drugs and targeted therapeutics.

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“…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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PI3Kγ ablation does not promote diabetes in db/db mice, 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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PI3Kα inhibition reduces obesity in mice

Cited by 21 publications

References 21 publications

Increased mitochondrial and lipid metabolism is a conserved effect of Insulin/PI3K pathway downregulation in adipose tissue

Increased mitochondrial and lipid metabolism is a conserved effect of Insulin/PI3K pathway downregulation in adipose tissue

Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells

PI3Kγ ablation does not promote diabetes in db/db mice, but improves insulin sensitivity and reduces pancreatic β‐cell apoptosis

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