FGF21 induces PGC-1⍺ and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response (Potthoff et al, 2009)

SNT Gatchaman

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FGF21 induces PGC-1⍺ and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response
Matthew J. Potthoff, Takeshi Inagaki, Santhosh Satapati, Xunshan Ding, Tianteng He, Regina Goetz, Moosa Mohammadi, Brian N. Finck, David J. Mangelsdorf, Steven A. Kliewer, Shawn C. Burgess

The liver plays a crucial role in mobilizing energy during nutritional deprivation. During the early stages of fasting, hepatic glycogenolysis is a primary energy source. As fasting progresses and glycogen stores are depleted, hepatic gluconeogenesis and ketogenesis become major energy sources.

Here, we show that fibroblast growth factor 21 (FGF21), a hormone that is induced in liver by fasting, induces hepatic expression of peroxisome proliferator-activated receptor-gamma-coactivator protein-1⍺ (PGC-1⍺), a key transcriptional regulator of energy homeostasis, and causes corresponding increases in fatty acid oxidation, tricarboxylic acid cycle flux, and gluconeogenesis without increasing glycogenolysis. Mice lacking FGF21 fail to fully induce PGC-1⍺ expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis.

These results reveal an unexpected relationship between FGF21 and PGC-1⍺ and demonstrate an important role for FGF21 in coordinately regulating carbohydrate and fatty acid metabolism during the progression from fasting to starvation.

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SNT Gatchaman

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FGF21 signals through cell-surface receptors composed of classic FGF receptors complexed with β-klotho, a membrane-spanning protein. Induction of FGF21 during fasting occurs through a mechanism that requires peroxisome proliferator-activated receptor-⍺ (PPAR⍺).
FGF21 has diverse metabolic actions that include stimulating hepatic fatty acid oxidation and ketogenesis and blocking the growth hormone signaling pathway. FGF21 also sensitizes mice to torpor, a short-term hibernation-like state of regulated hypothermia.
PGC-1⍺ is a transcriptional coactivator protein whose expression is induced in response to changes in nutritional status and other physiologic stimuli such as cold and exercise. PGC-1⍺ is enriched in metabolic tissues, such as muscle and heart, where it interacts with multiple DNA-binding transcription factors to stimulate mitochondrial metabolic capacity. In liver, induction of PGC-1⍺ by fasting stimulates the transcription of genes involved in fatty acid oxidation, tricarboxylic acid (TCA) cycle flux, mitochondrial oxidative phosphorylation, and gluconeogenesis.
FGF21 Stimulates a Fasting Metabolic State.
As expected, hepatic oxygen consumption was increased in response to fasting in WT liver. Importantly, FGF21-TG liver from fed mice exhibited increased oxygen consumption rates that were equivalent to those observed in WT fasted liver.
These data are consistent with the previous description of FGF21 as a ketogenic factor and provide additional evidence that FGF21 is critical for the induction of hepatic fat oxidation during fasting.
These data demonstrate that overexpression of FGF21 is sufficient to induce gluconeogenesis in the fed state to levels normally attained during prolonged fasting. The concept that FGF21 expression induces a metabolic state in liver that mimics long-term fasting was reinforced by impaired glycogenolysis.
...these data demonstrate that the coordinate effects of FGF21 on gluconeogenic gene expression require PGC-1⍺.
FGF21-KO Mice Have Metabolic Defects.
Plasma glucose levels, however, were significantly reduced in fasted FGF21-KO mice. Plasma ketone levels were significantly reduced in fed mice and trended lower in fasted FGF21-KO mice. FGF21-KO mice also showed trends toward increased plasma NEFA and triglyceride concentrations during fasting, suggesting that FGF21-KO mice may avoid overt hypoketosis during fasting by increasing lipid delivery to the liver.
Under fasted conditions, Cel, Pnlip, Pnliprp2, Pgc1⍺, G6pase, and Pepck mRNAs were induced in WT mice (Fig. 4). With the exception of Pepck, induction of all of these genes was significantly attenuated in liver of FGF21-KO mice.
Overall, these loss-of-function data demonstrate that FGF21 plays an important role in inducing PGC-1⍺ and other genes involved in regulating carbohydrate and lipid metabolism during fasting.
Remarkably, there was also no induction of gluconeogenesis in FGF21-KO liver in response to fasting. Neither glycogenolysis nor liver glycogen concentrations were significantly different between WT and FGF21-KO liver under fed or fasted conditions. The loss of fasting-induced gluconeogenesis in FGF21-KO mice is consistent with the hypoglycemia that occurs in these animals.
Thus, FGF21 is crucial for the liver’s adaptive metabolic response to prolonged fasting.
FGF21 is similar to the fasting hormone glucagon in that it induces hepatic gluconeogenesis, fatty acid oxidation, and ketogenesis. However, in marked contrast to glucagon, FGF21 does not promote glycogenolysis.
findings raise the possibility that FGF21 maintains gluconeogenesis and ketogenesis in the context of prolonged fasting and starvation, when glycogen stores are depleted and glucagon levels have fallen. In this model, glucagon and FGF21 are not redundant but rather sequential in their actions.
...findings raise the interesting possibility that FGF21 might induce Pgc1⍺ through an indirect mechanism involving the central nervous system.
FGF21 functions as a potent insulin sensitizer in various animal models of insulin resistance and diabetes.
Our data suggest that FGF21 does not improve glycemic control by suppressing hepatic gluconeogenesis per se. Rather, they indicate that FGF21 improves hepatic insulin action indirectly by stimulating hepatic fatty acid disposal.
 

Boba

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Me patients have the metabolic profile of starvation. I may self had changes in my thyroid hormones seen comparable to starving people. Are we starving even if we eat properly? Why are starving? Is it because our guts don’t absorb or because hormones or our cns are out of whack?