JNK1 ablation in mice confers long‐term metabolic protection from diet‐induced obesity at the cost of moderate skin oxidative damage

Becattini, Barbara; Zani, Fabio; Breasson, Ludovic; Sardi, Claudia; D’Agostino, Vito; Choo, Min‐Kyung; Provenzani, Alessandro; Park, Jin Mo; Solinas, Giovanni

doi:10.1096/fj.201600393r

Cited by 11 publications

(11 citation statements)

References 46 publications

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“…However, melittin, the main constituent of apitoxin, improves insulin sensitivity through the activation of phospholipase A2 in diabetic mice induced by diet [ 56 ]. Both apitoxin and melittin may have contributed to the glycemic control observed in this study, although insulin resistance is the predominant mechanism that triggers diet-induced diabetes [ 57 , 58 , 59 ], which was the model used in this study.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant, antihyperglycemic, and antidiabetic activity of Apis mellifera bee tea

et al. 2018

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Diabetes has emerged as one of the largest global epidemics; it is estimated that by 2035, there will be 592 million diabetic people in the world. Brazilian biodiversity and the knowledge of traditional peoples have contributed to the treatment of several diseases, including diabetes. Apis mellifera bee tea is used by indigenous Brazilians to treat diabetes, and this traditional knowledge needs to be recorded and studied.The objective of this study was to record the use and to evaluate the antioxidant, antihyperglycemic, and antidiabetic activity of Apis mellifera bee tea, which is used by the Guarani and Kaiowá indigenous people for the treatment of diabetes. Semi-structured interviews were performed with Guarani and Kaiowá ethnic indigenous people from the State of Mato Grosso do Sul, Brazil, seeking to identify the animal species used for medicinal purposes. For the experimental procedures, tea prepared with macerated Apis mellifera bees was used. In vitro assays were performed to evaluate antioxidant activity; direct free radical scavenging, protection against oxidative hemolysis, lipid peroxidation were evaluated in human erythrocytes and potential in inhibiting the formation of advanced glycation end products (AGEs). In vivo, normoglycemic Swiss male mice treated with Apis mellifera tea (AmT) were subjected to the oral glucose tolerance test and compared with control and metformin-treated groups. Diet-induced diabetic mice were treated for 21 days with AmT and evaluated for glycemia and malondialdehyde levels in the blood, liver, nervous system, and eyes. During interviews, the indigenous people described the use of Apis mellifera bee tea for the treatment of diabetes. In in vitro assays, AmT showed direct antioxidant activity and reduced oxidative hemolysis and malondialdehyde generation in human erythrocytes. The AmT inhibited the formation of AGEs by albumin-fructose pathways and methylglyoxal products. In vivo, after oral glucose overload, normoglycemic mice treated with AmT had reduced hyperglycemia at all times evaluated up to 180 min. AmT also reduced hyperglycemia and malondialdehyde levels in the blood, liver, nervous system, and eyes of diabetic mice to similar levels as those in metformin-treated mice and normoglycemic controls. In summary, Apis mellifera bee tea showed antioxidant, antihyperglycemic, and antidiabetic activity, which provides support for the therapeutic application of Guarani and Kaiowá indigenous knowledge.

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Section: Discussionmentioning

confidence: 99%

Antioxidant, antihyperglycemic, and antidiabetic activity of Apis mellifera bee tea

et al. 2018

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“…To learn about the long-term effects of JNK1 ablation in mammals undergoing metabolic stress from obesity, we have investigated mice lacking JNK1 (JNK1 −/− ) that are chronically fed an obesogenic high-fat diet for the duration of their lifetime [82] . The results showed that, compared to control mice, JNK1 −/− mice maintained on high-fat diet display normal life-span and long-term sustained protection from obesity, hepatic lipid accumulation, adipose tissue inflammation, and insulin resistance.…”

Section: Role Of Jnk In the Cell Response To Metabolic Stress: Emergimentioning

confidence: 99%

“…Measurement of lipid peroxidation in different tissues showed that oxidative damage in JNK1 −/− mice fed a high-fat diet for 40 weeks was similar-to-controls in kidney and heart, slightly improved in the liver and largely improved in adipose tissue, but was significantly worsened in the skin. The protective effects of JNK1 ablation on liver and fat oxidative stress were proposed to be, at least in part, a consequence of the reduced steatosis and reduced adipose tissue inflammation, whereas increased skin oxidative damage was correlated with a local reduction of the expression of antioxidant genes [82] .…”

Section: Role Of Jnk In the Cell Response To Metabolic Stress: Emergimentioning

confidence: 99%

JNK at the crossroad of obesity, insulin resistance, and cell stress response

Solinas

Becattini

2017

Molecular Metabolism

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BackgroundThe cJun-N-terminal-kinase (JNK) plays a central role in the cell stress response, with outcomes ranging from cell death to cell proliferation and survival, depending on the specific context. JNK is also one of the most investigated signal transducers in obesity and insulin resistance, and studies have identified new molecular mechanisms linking obesity and insulin resistance. Emerging evidence indicates that whereas JNK1 and JNK2 isoforms promote the development of obesity and insulin resistance, JNK3 activity protects from excessive adiposity. Furthermore, current evidence indicates that JNK activity within specific cell types may, in specific stages of disease progression, promote cell tolerance to the stress associated with obesity and type-2 diabetes.Scope of reviewThis review provides an overview of the current literature on the role of JNK in the progression from obesity to insulin resistance, NAFLD, type-2 diabetes, and diabetes complications.Major conclusionWhereas current evidence indicates that JNK1/2 inhibition may improve insulin sensitivity in obesity, the role of JNK in the progression from insulin resistance to diabetes, and its complications is largely unresolved. A better understanding of the role of JNK in the stress response to obesity and type-2 diabetes, and the development of isoform-specific inhibitors with specific tissue distribution will be necessary to exploit JNK as possible drug target for the treatment of type-2 diabetes.

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“…39 Total RNA quality and quantity was evaluated on a denaturing agarose gel. RNA was retro-transcribed using a commercial kit (Promega), and cDNA used to perform real-time quantitative PCR using a commercial SYBR-Green mix (Biorad) and specific primer sequences 11,40,41 listed in Table S1. For immunostaining, after fixation in 4% buffered formaldehyde, liver and fat tissues were embedded in paraffin, and cut into 5 µm thick sections.…”

Section: Molecular and Histopathological Analysis Of Liver And Adipmentioning

confidence: 99%

“…2 Because of the importance of the context in determining the outcome of JNK signaling in stress response, it is necessary to evaluate the effects of JNK inactivation on different stages of the progression of obesity-driven diabetes. However, while the role of different JNK isoforms in obesity-driven insulin resistance has been extensively investigated, 6,7,[9][10][11][12][13][14][15][16][17][18][19][20] the effects of JNK ablation on obesity-driven loss of functional pancreatic β-cells was not investigated to the same extent.…”

Section: Introductionmentioning

confidence: 99%

JNK1 ablation improves pancreatic β‐cell mass and function in db/db diabetic mice without affecting insulin sensitivity and adipose tissue inflammation

et al. 2020

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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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JNK1 ablation in mice confers long‐term metabolic protection from diet‐induced obesity at the cost of moderate skin oxidative damage

Cited by 11 publications

References 46 publications

Antioxidant, antihyperglycemic, and antidiabetic activity of Apis mellifera bee tea

Antioxidant, antihyperglycemic, and antidiabetic activity of Apis mellifera bee tea

JNK at the crossroad of obesity, insulin resistance, and cell stress response

JNK1 ablation improves pancreatic β‐cell mass and function in db/db diabetic mice without affecting insulin sensitivity and adipose tissue inflammation

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