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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

Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice

Satish Patel, Afreen Haider, Anna Alvarez-Guaita, Guillaume Bidault, ... David B. Savage

Objectives

Obesity in humans and mice is associated with elevated levels of two hormones responsive to cellular stress, namely GDF15 and FGF21. Over-expression of each of these is associated with weight loss and beneficial metabolic changes but where they are secreted from and what they are required for physiologically in the context of overfeeding remains unclear.

Methods

Here we used tissue selective knockout mouse models and human transcriptomics to determine the source of circulating GDF15 in obesity. We then generated and characterized the metabolic phenotypes of GDF15/FGF21 double knockout mice.

Results

Circulating GDF15 and FGF21 are both largely derived from the liver, rather than adipose tissue or skeletal muscle, in obese states. Combined whole body deletion of FGF21 and GDF15 does not result in any additional weight gain in response to high fat feeding but it does result in significantly greater hepatic steatosis and insulin resistance than that seen in GDF15 single knockout mice.

Conclusions

Collectively the data suggest that overfeeding activates a stress response in the liver which is the major source of systemic rises in GDF15 and FGF21. These hormones then activate pathways which reduce this metabolic stress.

Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice

Satish Patel, Afreen Haider, Anna Alvarez-Guaita, Guillaume Bidault, ... David B. Savage

Objectives

Obesity in humans and mice is associated with elevated levels of two hormones responsive to cellular stress, namely GDF15 and FGF21. Over-expression of each of these is associated with weight loss and beneficial metabolic changes but where they are secreted from and what they are required for physiologically in the context of overfeeding remains unclear.

Methods

Here we used tissue selective knockout mouse models and human transcriptomics to determine the source of circulating GDF15 in obesity. We then generated and characterized the metabolic phenotypes of GDF15/FGF21 double knockout mice.

Results

Circulating GDF15 and FGF21 are both largely derived from the liver, rather than adipose tissue or skeletal muscle, in obese states. Combined whole body deletion of FGF21 and GDF15 does not result in any additional weight gain in response to high fat feeding but it does result in significantly greater hepatic steatosis and insulin resistance than that seen in GDF15 single knockout mice.

Conclusions

Collectively the data suggest that overfeeding activates a stress response in the liver which is the major source of systemic rises in GDF15 and FGF21. These hormones then activate pathways which reduce this metabolic stress.

2021 impact factor: 8.568

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