| 1. |
- Becattini, Barbara, et al.
(författare)
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Adipocyte PI3K links adipostasis with baseline insulin secretion at fasting through an adipoincretin effect.
- 2024
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Ingår i: Cell reports. - 2211-1247. ; 43:5
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-PI3K signaling controls insulin secretion. Understanding this feedback mechanism is crucial for comprehending how insulin functions. However, the role of adipocyte insulin-PI3K signaling in controlling insulin secretion invivo remains unclear. Using adipocyte-specific PI3Kα knockout mice (PI3KαAdQ) and a panel of isoform-selective PI3K inhibitors, we show that PI3Kα and PI3Kβ activities are functionally redundant in adipocyte insulin signaling. PI3Kβ-selective inhibitors have no effect on adipocyte AKT phosphorylation in control mice but blunt it in adipocytes of PI3KαAdQ mice, demonstrating adipocyte-selective pharmacological PI3K inhibition in the latter. Acute adipocyte-selective PI3K inhibition increases serum free fatty acid (FFA) and potently induces insulin secretion. We name this phenomenon the adipoincretin effect. The adipoincretin effect operates in fasted mice with increasing FFA and decreasing glycemia, indicating that it is not primarily a control system for blood glucose. This feedback control system defines the rates of adipose tissue lipolysis and chiefly controls basal insulin secretion during fasting.
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| 2. |
- Becattini, Barbara, et al.
(författare)
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PI3K gamma promotes obesity-associated hepatocellular carcinoma by regulating metabolism and inflammation
- 2021
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Ingår i: Jhep Reports. - : Elsevier BV. - 2589-5559. ; 3:6
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Phosphatidylinositides-3 kinases (PI3Ks) are promising drug targets for cancer therapy, but blockage of PI3K-AKT signalling causes hyperglycaemia, hyperinsulinaemia, and liver damage in patients, and hepatocellular carcinoma (HCC) in mice. There are 4 PI3K alpha: PI3K beta, PI3K delta, PI3K gamma, and PI3K gamma. The role of PI3K gamma in HCC is unknown. Methods: We performed histopathological, metabolic, and molecular phenotyping of mice with genetic ablation of PI3K gamma using models where HCC was initiated by the carcinogen diethylnitrosamine (DEN) and promoted by dietary or genetic obesity (ob/ob). The role of PI3K gamma in leucocytes was investigated in mice lacking PI3K gamma in haematopoietic and endothelial cells. Results: Loss of PI3K gamma had no effects on the development of DEN-induced HCC in lean mice. However, in mice injected with DEN and placed on an obesogenic diet, PI3K gamma ablation reduced tumour growth, which was associated with reduced insulinaemia, steatosis, and expression of inflammatory cytokines. ob/ob mice lacking PI3K gamma, and mice with diet-induced obesity lacking PI3K gamma in leucocytes and endothelial cells did not display improved insulin sensitivity, steatosis, metabolic inflammation, or reduced tumour growth. However, these mice showed a reduced number of tumours, reduced liver infiltration by neutrophils, and reduced hepatocyte proliferation acutely induced by DEN. Conclusions: Loss of PI3K gamma reduces tumour development in obesity-promoted HCC through multiple cell types and mechanisms that include improved insulinaemia, steatosis, and metabolic inflammation as well as the regulation of acute neutrophil infiltration and compensatory hepatocyte proliferation. PI3K gamma-selective inhibition may represent a novel therapeutic approach to reduce HCC initiation and slow HCC progression. Lay summary: Class-1 phosphatidylinositides-3 kinases (PI3K gamma) are critical targets in cancer therapy, but complete inhibition of all isoforms causes liver damage, hyperglycaemia, and insulinaemia. Here we show that selective ablation of the PI3K gamma isoform dampens tumour initiation and growth in a mouse model of carcinogen-initiated and obesity-promoted hepatocellular carcinoma (HCC). The effect of PI3K gamma ablation on reduced tumour growth was explained by reduced tumour cell proliferation, which was associated with reduced insulin levels, liver lipids, and reduced expression of tumour-promoting cytokines. PI3K gamma ablation in leucocytes of obese mice had no effects on tumour size. However, it reduced tumour number in association with reduced carcinogen-induced neutrophil infiltration and hepatocyte proliferation in livers of obese mice. Inhibition of PI3K gamma may thus reduce HCC initiation and growth in obese subjects by a mechanism involving reduced metabolic stress and insulinaemia and reduced carcinogen-induced neutrophil infiltration to the fatty liver. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL).
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| 3. |
- Becattini, Barbara, et al.
(författare)
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PI3Kγ within a Nonhematopoietic Cell Type Negatively Regulates Diet-Induced Thermogenesis and Promotes Obesity and Insulin Resistance.
- 2011
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Ingår i: Proceedings of the National Academy of Science of the United States of America. - 0027-8424 .- 1091-6490. ; 108:42
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Tidskriftsartikel (refereegranskat)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.
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| 4. |
- Breasson, Ludovic, et al.
(författare)
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PI3K gamma ablation does not promote diabetes in db/db mice, but improves insulin sensitivity and reduces pancreatic beta-cell apoptosis
- 2018
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Ingår i: Faseb Journal. - 0892-6638. ; 32:1
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Tidskriftsartikel (refereegranskat)abstract
- PI3K gamma has emerged as a promising target for the treatment of obesity and insulin resistance; however, previous studies have indicated that PI3K gamma activity in pancreatic beta 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 beta-cell function is a major concern for the pharmacologic inhibition of PI3K gamma. To address this issue, we investigated the effects of PI3K gamma ablation in db/db diabetic mice, a genetic model of obesity-driven beta-cell failure and diabetes. Mice that lacked PI3K gamma were backcrossed into db/+ mice C57BL/KS (>10 generations) to obtain db/db-PI3K gamma(-/-) mice. db/db-PI3K gamma(-/-) mice and control db/db mice were phenotyped for glucose homeostasis, insulin sensitivity, insulin secretion, steatosis, metabolic inflammation, pancreatic islet morphometry, islet cellular composition, and inflammation. Pancreatic beta-cell apoptosis and proliferation were also evaluated. db/db-PI3K gamma(-/-) mice and control db/db mice developed similar body weight, steatosis, glycemia, and insulin levels after a glucose load; however, db/db-PI3K gamma(-/-) mice displayed improved insulin tolerance, higher levels of fasting seruminsulin, and lower pancreatic insulin content. In db/db-PI3K gamma(-/-) 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, db/db-PI3K gamma(-/-) mice have more pancreatic beta cells and larger islets than db/db mice, despite displaying similar islet inflammation. This phenotype could be explained by reduced beta-cell apoptosis in db/db-PI3K gamma(-/-) mice compared with control db/db mice. Our results are consistent with the concept that the beneficial action of PI3K gamma 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 PI3K gamma is required for insulin secretion in response to glucose in vivo, and indicate that PI3K gamma ablation protects db/db mice from beta-cell apoptosis and improves fasting insulin levels. We conclude that PI3K gamma inhibition in obese patients who are predisposed to beta-cell failure is not expected to produce adverse effects on insulin secretion.
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| 5. |
- Breasson, Ludovic, et al.
(författare)
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PI3Kγ activity in leukocytes promotes adipose tissue inflammation and early-onset insulin resistance during obesity.
- 2017
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Ingår i: Science signaling. - : American Association for the Advancement of Science (AAAS). - 1937-9145 .- 1945-0877. ; 10:488
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Tidskriftsartikel (refereegranskat)abstract
- The phosphoinositide 3-kinase γ (PI3Kγ) plays a major role in leukocyte recruitment during acute inflammation and has been proposed to inhibit classical macrophage activation by driving immunosuppressive gene expression. PI3Kγ plays an important role in diet-induced obesity and insulin resistance. In seeking to determine the underlying molecular mechanisms, we showed that PI3Kγ action in high-fat diet-induced inflammation and insulin resistance depended largely on its role in the control of adiposity, which was due to PI3Kγ activity in a nonhematopoietic cell type. However, PI3Kγ activity in leukocytes was required for efficient neutrophil recruitment to adipose tissue. Neutrophil recruitment was correlated with proinflammatory gene expression in macrophages in adipose tissue, which triggered insulin resistance early during the development of obesity. Our data challenge the concept that PI3Kγ is a general suppressor of classical macrophage activation and indicate that PI3Kγ controls macrophage gene expression by non-cell-autonomous mechanisms, the outcome of which is context-dependent.
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| 6. |
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| 7. |
- Engström-Ruud, Linda, et al.
(författare)
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Activation of GFRAL+ neurons induces hypothermia and glucoregulatory responses associated with nausea and torpor.
- 2024
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Ingår i: Cell reports. - 2211-1247. ; 43:4
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Tidskriftsartikel (refereegranskat)abstract
- GFRAL-expressing neurons actuate aversion and nausea, are targets for obesity treatment, and may mediate metformin effects by long-term GDF15-GFRAL agonism. Whether GFRAL+ neurons acutely regulate glucose and energy homeostasis is, however, underexplored. Here, we report that cell-specific activation of GFRAL+ neurons using a variety of techniques causes a torpor-like state, including hypothermia, the release of stress hormones, a shift from glucose to lipid oxidation, and impaired insulin sensitivity, glucose tolerance, and skeletal muscle glucose uptake but augmented glucose uptake in visceral fat. Metabolomic analysis of blood and transcriptomics of muscle and fat indicate alterations in ketogenesis, insulin signaling, adipose tissue differentiation and mitogenesis, and energy fluxes. Our findings indicate that acute GFRAL+ neuron activation induces endocrine and gluco- and thermoregulatory responses associated with nausea and torpor. While chronic activation of GFRAL signaling promotes weight loss in obesity, these results show that acute activation of GFRAL+ neurons causes hypothermia and hyperglycemia.
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| 8. |
- Fryk, Emanuel, et al.
(författare)
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Hyperinsulinemia and insulin resistance in the obese may develop as part of a homeostatic response to elevated free fatty acids: A mechanistic case-control and a population-based cohort study
- 2021
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Ingår i: Ebiomedicine. - : Elsevier BV. - 2352-3964. ; 65
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is commonly accepted that in obesity free fatty acids (FFA) cause insulin resistance and hyperglycemia, which drives hyperinsulinemia. However, hyperinsulinemia is observed in subjects with normoglycaemia and thus the paradigm above should be reevaluated. Methods: We describe two studies: MD-Lipolysis, a case control study investigating the mechanisms of obesity-driven insulin resistance by a systemic metabolic analysis, measurements of adipose tissue lipolysis by microdialysis, and adipose tissue genomics; and POEM, a cohort study used for validating differences in circulating metabolites in relation to adiposity and insulin resistance observed in the MD-Lipolysis study. Findings: In insulin-resistant obese with normal glycaemia from the MD-Lipolysis study, hyperinsulinemia was associated with elevated FFA. Lipolysis, assessed by glycerol release per adipose tissue mass or adipocyte surface, was similar between obese and lean individuals. Adipose tissue from obese subjects showed reduced expression of genes mediating catecholamine-driven lipolysis, lipid storage, and increased expression of genes driving hyperplastic growth. In the POEM study, FFA levels were specifically elevated in obese-overweight subjects with normal fasting glucose and high fasting levels of insulin and C-peptide. Interpretation: In obese subjects with normal glycaemia elevated circulating levels of FFA at fasting are the major metabolic derangement candidate driving fasting hyperinsulinemia. Elevated FFA in obese with normal glycaemia were better explained by increased fat mass rather than by adipose tissue insulin resistance. These results support the idea that hyperinsulinemia and insulin resistance may develop as part of a homeostatic adaptive response to increased adiposity and FFA. (C) 2021 The Author(s). Published by Elsevier B.V.
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| 9. |
- Mancina, Rosellina Margherita, et al.
(författare)
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PSD3 downregulation confers protection against fatty liver disease.
- 2022
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 4:1, s. 60-75
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Tidskriftsartikel (refereegranskat)abstract
- Fatty liver disease (FLD) is a growing health issue with burdening unmet clinical needs. FLD has a genetic component but, despite the common variants already identified, there is still a missing heritability component. Using a candidate gene approach, we identify a locus (rs71519934) at the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene resulting in a leucine to threonine substitution at position 186 of the protein (L186T) that reduces susceptibility to the entire spectrum of FLD in individuals at risk. PSD3 downregulation by short interfering RNA reduces intracellular lipid content in primary human hepatocytes cultured in two and three dimensions, and in human and rodent hepatoma cells. Consistent with this, Psd3 downregulation by antisense oligonucleotides in vivo protects against FLD in mice fed a non-alcoholic steatohepatitis-inducing diet. Thus, translating these results to humans, PSD3 downregulation might be a future therapeutic option for treating FLD.
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| 10. |
- Mazzoli, Arianna, et al.
(författare)
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JNK1 ablation improves pancreatic β-cell mass and function in db/db diabetic mice without affecting insulin sensitivity and adipose tissue inflammation.
- 2021
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Ingår i: FASEB bioAdvances. - : Wiley. - 2573-9832. ; 3:2, s. 94-107
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Tidskriftsartikel (refereegranskat)abstract
- The cJun N-terminal Kinases (JNK) emerged as a major link between obesity and insulin resistance, but their role in the loss of pancreatic β-cell mass and function driving the progression from insulin resistance to type-2 diabetes and in the complications of diabetes was not investigated to the same extent. Furthermore, it was shown that pan-JNK inhibition exacerbates kidney damage in the db/db model of obesity-driven diabetes. Here we investigate the role of JNK1 in the db/db model of obesity-driven type-2 diabetes. Mice with systemic ablation of JNK1 (JNK1-/-) were backcrossed for more than 10 generations in db/+ C57BL/KS mice to generate db/db-JNK1-/- mice and db/db control mice. To define the role of JNK1 in the loss of β-cell mass and function occurring during obesity-driven diabetes we performed comprehensive metabolic phenotyping, evaluated steatosis and metabolic inflammation, performed morphometric and cellular composition analysis of pancreatic islets, and evaluated kidney function in db/db-JNK1-/- mice and db/db controls. db/db-JNK1-/- mice and db/db control mice developed insulin resistance, fatty liver, and metabolic inflammation to a similar extent. However, db/db-JNK1-/- mice displayed better glucose tolerance and improved insulin levels during glucose tolerance test, higher pancreatic insulin content, and larger pancreatic islets with more β-cells than db/db mice. Finally, albuminuria, kidney histopathology, kidney inflammation and oxidative stress in db/db-JNK1-/- mice and in db/db mice were similar. Our data indicate that selective JNK1 ablation improves glucose tolerance in db/db mice by reducing the loss of functional β-cells occurring in the db/db mouse model of obesity-driven diabetes, without significantly affecting metabolic inflammation, steatosis, and insulin sensitivity. Furthermore, we have found that, differently from what previously reported for pan-JNK inhibitors, selective JNK1 ablation does not exacerbate kidney dysfunction in db/db mice. We conclude that selective JNK1 inactivation may have a superior therapeutic index than pan-JNK inhibition in obesity-driven diabetes.
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