Cover Story Current Issue

Cancer cachexia is a systemic metabolic dysfunction that affects more than 80% of pancreatic cancer patients and is the leading cause of death in 22%–30% of all cancers. Because the cancer spread beyond the pancreas at the time of diagnosis, only about 20% of patients are candidates for surgery. Pancreatic cancer's aggressiveness destabilizes whole-body homeostasis by dismantling the normal network of organs crosstalk. This miss-communication favors the tumor progression during cancer cachexia, which is characterized by devastating body weight lossmuscle atrophy, fat wasting, decreased appetite. The molecular mechanisms underlying these metabolic cues are still being investigated.

Mengistu Lemecha, Jaya Prakash Chalise, Yuki Takamuku, Guoxiang Zhang, ... Keiichi Itakura

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Current Issue

Genetic disruption of the Gipr in Apoe−/− mice promotes atherosclerosis

Gemma Pujadas, Laurie L. Baggio, Kiran Deep Kaur, Brent A. McLean, ... Daniel J. Drucker

Objective

The gut hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates beta cell function and improves glycemia through its incretinactions. GIP also regulates endothelial function and suppresses adipose tissueinflammation through control of macrophage activity. Activation of the GIP receptor (GIPR) attenuates experimental atherosclerosis and inflammation in mice, however whether loss of GIPR signaling impacts the development of atherosclerosis is uncertain.

Methods

Atherosclerosis and related metabolic phenotypes were studied in Apoe−/−:Gipr−/− mice and in Gipr+/+ and Gipr−/− mice treated with an adeno-associated virus expressing PCSK9 (AAV-PCSK9). Bone marrow transplantation (BMT) studies were carried out using donor marrow from Apoe−/−:Gipr−/−and Apoe−/−:Gipr+/+mice transplanted into Apoe−/−:Gipr−/− recipient mice. Experimental endpoints included the extent of aortic atherosclerosis and inflammation, body weight, glucose tolerance, and circulating lipid levels, the proportions and subsets of circulating leukocytes, and tissue gene expression profiles informing lipid and glucose metabolism, and inflammation.

Results

Body weight was lower, circulating myeloid cells were reduced, and glucose tolerance was not different, however, aortic atherosclerosis was increased in Apoe−/−:Gipr−/− mice and trended higher in Gipr−/− mice with atherosclerosis induced by AAV-PCSK9. Levels of mRNA transcripts for genes contributing to inflammation were increased in the aortae of Apoe−/−:Gipr−/− mice and expression of a subset of inflammation-related hepatic genes were increased in Gipr−/− mice treated with AAV-PCSK9. BMT experiments did not reveal marked atherosclerosis, failing to implicate bone marrow derived GIPR + cells in the control of atherosclerosis or aortic inflammation.

Conclusions

Loss of the Gipr in mice results in increased aortic atherosclerosis and enhanced inflammation in aorta and liver, despite reduced weight gain and preserved glucose homeostasis. These findings extend concepts of GIPR in the suppression of inflammation-related pathophysiology beyond its classical incretin role in the control of metabolism.

Genetic disruption of the Gipr in Apoe−/− mice promotes atherosclerosis

Gemma Pujadas, Laurie L. Baggio, Kiran Deep Kaur, Brent A. McLean, ... Daniel J. Drucker

Objective

The gut hormone glucose-dependent insulinotropic polypeptide (GIP) stimulates beta cell function and improves glycemia through its incretinactions. GIP also regulates endothelial function and suppresses adipose tissueinflammation through control of macrophage activity. Activation of the GIP receptor (GIPR) attenuates experimental atherosclerosis and inflammation in mice, however whether loss of GIPR signaling impacts the development of atherosclerosis is uncertain.

Methods

Atherosclerosis and related metabolic phenotypes were studied in Apoe−/−:Gipr−/− mice and in Gipr+/+ and Gipr−/− mice treated with an adeno-associated virus expressing PCSK9 (AAV-PCSK9). Bone marrow transplantation (BMT) studies were carried out using donor marrow from Apoe−/−:Gipr−/−and Apoe−/−:Gipr+/+mice transplanted into Apoe−/−:Gipr−/− recipient mice. Experimental endpoints included the extent of aortic atherosclerosis and inflammation, body weight, glucose tolerance, and circulating lipid levels, the proportions and subsets of circulating leukocytes, and tissue gene expression profiles informing lipid and glucose metabolism, and inflammation.

Results

Body weight was lower, circulating myeloid cells were reduced, and glucose tolerance was not different, however, aortic atherosclerosis was increased in Apoe−/−:Gipr−/− mice and trended higher in Gipr−/− mice with atherosclerosis induced by AAV-PCSK9. Levels of mRNA transcripts for genes contributing to inflammation were increased in the aortae of Apoe−/−:Gipr−/− mice and expression of a subset of inflammation-related hepatic genes were increased in Gipr−/− mice treated with AAV-PCSK9. BMT experiments did not reveal marked atherosclerosis, failing to implicate bone marrow derived GIPR + cells in the control of atherosclerosis or aortic inflammation.

Conclusions

Loss of the Gipr in mice results in increased aortic atherosclerosis and enhanced inflammation in aorta and liver, despite reduced weight gain and preserved glucose homeostasis. These findings extend concepts of GIPR in the suppression of inflammation-related pathophysiology beyond its classical incretin role in the control of metabolism.

2021 impact factor: 8.568

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