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

Full text

 

Current Issue

GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein

Simon Hoffman, Danielle Alvares, Khosrow Adeli

Background/Objective

GLP-1R agonists have been shown to reduce fasting and postprandial plasma lipids, both of which are independent risk factors for the development of cardiovascular disease. However, how endogenous GLP-1 – which is rapidly degraded – modulates intestinal and hepatic lipid metabolism is less clear. A vagal gut-brain-axis originating in the portal vein has been proposed as a possible mechanism for GLP-1’s anti-lipemic effects. Here we sought to examine the relationship between vagal GLP-1 signalling and intestinal lipid absorption and lipoprotein production.

Methods

Syrian golden hamsters or C57BL/6 mice received portal vein injections of GLP-1(7-36), and postprandial and fasting plasma TG, TRL TG, or VLDL TG were examined. These experiments were repeated during sympathetic blockade, and under a variety of pharmacological or surgical deafferentation techniques. In addition, hamsters received nodose ganglia injections of a GLP-1R agonist or antagonist to further probe the vagal pathway. Peripheral studies were repeated in a novel GLP-1R KO hamster model and in our diet-induced hamster models of insulin resistance.

Results

GLP-1(7-36) site-specifically reduced postprandial and fasting plasma lipids in both hamsters and mice. These inhibitory effects of GLP-1 were investigated via pharmacological and surgical denervation experiments and found to be dependent on intact afferent vagal signalling cascades and efferent changes in sympathetic tone. Furthermore, GLP-1R agonism in the nodose ganglia resulted in markedly reduced postprandial plasma TG and TRL TG, and fasting VLDL TG and this nodose GLP-1R activity was essential for portal GLP-1s effect. Notably, portal and nodose ganglia GLP-1 effects were lost in GLP-1R KO hamsters and following diet-induced insulin resistance.

Conclusion

Our data demonstrates for the first time that portal GLP-1 modulates postprandial and fasting lipids via a complex vagal gut–brain–liver axis. Importantly, loss or interference with this signalling axis via surgical, pharmacological, or dietary intervention resulted in the loss of portal GLP-1s anti-lipemic effects. This supports emerging evidence that native GLP-1 works primarily through a vagal neuroendocrine mechanism.

GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein

Simon Hoffman, Danielle Alvares, Khosrow Adeli

Background/Objective

GLP-1R agonists have been shown to reduce fasting and postprandial plasma lipids, both of which are independent risk factors for the development of cardiovascular disease. However, how endogenous GLP-1 – which is rapidly degraded – modulates intestinal and hepatic lipid metabolism is less clear. A vagal gut-brain-axis originating in the portal vein has been proposed as a possible mechanism for GLP-1’s anti-lipemic effects. Here we sought to examine the relationship between vagal GLP-1 signalling and intestinal lipid absorption and lipoprotein production.

Methods

Syrian golden hamsters or C57BL/6 mice received portal vein injections of GLP-1(7-36), and postprandial and fasting plasma TG, TRL TG, or VLDL TG were examined. These experiments were repeated during sympathetic blockade, and under a variety of pharmacological or surgical deafferentation techniques. In addition, hamsters received nodose ganglia injections of a GLP-1R agonist or antagonist to further probe the vagal pathway. Peripheral studies were repeated in a novel GLP-1R KO hamster model and in our diet-induced hamster models of insulin resistance.

Results

GLP-1(7-36) site-specifically reduced postprandial and fasting plasma lipids in both hamsters and mice. These inhibitory effects of GLP-1 were investigated via pharmacological and surgical denervation experiments and found to be dependent on intact afferent vagal signalling cascades and efferent changes in sympathetic tone. Furthermore, GLP-1R agonism in the nodose ganglia resulted in markedly reduced postprandial plasma TG and TRL TG, and fasting VLDL TG and this nodose GLP-1R activity was essential for portal GLP-1s effect. Notably, portal and nodose ganglia GLP-1 effects were lost in GLP-1R KO hamsters and following diet-induced insulin resistance.

Conclusion

Our data demonstrates for the first time that portal GLP-1 modulates postprandial and fasting lipids via a complex vagal gut–brain–liver axis. Importantly, loss or interference with this signalling axis via surgical, pharmacological, or dietary intervention resulted in the loss of portal GLP-1s anti-lipemic effects. This supports emerging evidence that native GLP-1 works primarily through a vagal neuroendocrine mechanism.

2021 impact factor: 8.568

Here is a video of Vimeo. When the iframes is activated, a connection to Vimeo is established and, if necessary, cookies from Vimeo are also used. For further information on cookies policy click here.