Fibroblast Growth Factor 21-Deficient Mice Demonstrate Impaired Adaptation to Ketosis

Badman, Michael K.; Köester, Anja; Flier, Jeffrey S.; Kharitonenkov, Alexei; Maratos–Flier, Eleftheria

doi:10.1210/en.2009-0532

Cited by 321 publications

(306 citation statements)

References 27 publications

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“…Previous studies from our laboratory and others have demonstrated that modulation of FGF21 levels either via pharmacology or using molecular interventions lead to a phenotype similar to that seen with TR␤ agonist treatment i.e. a significant improvement in serum lipid profile (10,22), increased rates of lipolysis, and an increase in liver fatty acid metabolism (4,32). These findings suggest that stimulation of lipolysis and hepatic fatty acid oxidation via FGF21 induction using TR␤-specific agonists has significant therapeutic potential.…”

Section: Discussionmentioning

confidence: 95%

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Adams

Astapova

Fisher

et al. 2010

Journal of Biological Chemistry

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122

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Thyroid hormone has profound and diverse effects on liver metabolism. Here we show that tri-iodothyronine (T3) treatment in mice acutely and specifically induces hepatic expression of the metabolic regulator fibroblast growth factor 21 (FGF21). Mice treated with T3 showed a dose-dependent increase in hepatic FGF21 expression with significant induction at doses as low as 100 g/kg. Time course studies determined that induction is seen as early as 4 h after treatment with a further increase in expression at 6 h after injection. As FGF21 expression is downstream of the nuclear receptor peroxisome proliferatoractivated receptor ␣ (PPAR␣), we treated PPAR␣ knock-out mice with T3 and found no increase in expression, indicating that hepatic regulation of FGF21 by T3 in liver is via a PPAR␣-dependent mechanism. In contrast, in white adipose tissue, FGF21 expression was suppressed by T3 treatment, with other T3 targets unaffected. In cell culture studies with an FGF21 reporter construct, we determined that three transcription factors are required for induction of FGF21 expression: thyroid hormone receptor ␤ (TR␤), retinoid X receptor (RXR), and PPAR␣. These findings indicate a novel regulatory pathway whereby T3 positively regulates hepatic FGF21 expression, presenting a novel therapeutic target for diseases such as non-alcoholic fatty liver disease.The biochemical pathways mediating the metabolism of carbohydrates, lipids, and proteins are all regulated to some degree by thyroid hormone and the thyroid hormone receptors (␣ and ␤) (1, 2), which belong to the nuclear hormone receptor superfamily (1). In the liver, the ␤ isoform of the thyroid hormone receptor (TR␤) is responsible for mediating the majority of the actions of tri-iodothyronine (T3), 2 whereas in other tissues such as the heart and brown adipose tissue, the ␣ isoform (TR␣) is the main mediator of thyroid hormone effects (3, 4). FGF21 is a member of the endocrine FGF subfamily, which also includes FGF19 and FGF23, all of which circulate and have hormone-like actions (5, 6). FGF21 is known to stimulate glucose uptake in mouse 3T3-L1 adipocytes and in primary cultures of human adipocytes and can improve glucose homeostasis when administered to obese mice (6) and non-human primates (7). Transgenic mice overexpressing FGF21 in liver display improved insulin sensitivity and glucose clearance, reduced plasma triglyceride concentrations, and are resistant to weight gain when fed a high fat diet (6).Subsequent studies showed that administration of FGF21 to mice with high fat diet-induced obesity led to increased fat utilization and energy expenditure and reduced plasma glucose, insulin, serum lipid concentrations, and hepatic triglyceride concentrations (6,8). In one study, it was shown that the decrease in hepatic triglyceride concentrations was accompanied by a decrease in lipogenic gene expression (8).FGF21 expression is known to be downstream of the nuclear receptor PPAR␣, which itself plays a significant role in lipid oxidation. FGF21 is physiologically induced u...

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Section: Discussionmentioning

confidence: 95%

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Adams

Astapova

Fisher

et al. 2010

Journal of Biological Chemistry

Self Cite

122

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“…In transgenic mice, overexpression of Fgf21 improves insulin sensitivity and lowers glucose concentration (45). However, Fgf21 global knockout did not show a diabetic phenotype, although mice displayed a defect in lipid metabolism upon ketogenic diet treatment (46). In diabetic and obese conditions, both Fgf21 mRNA and serum FGF21 levels are paradoxically elevated, indicative of development of peripheral FGF21 resistance in the context of obesity (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Recruitment of Histone Methyltransferase G9a Mediates Transcriptional Repression of Fgf21 Gene by E4BP4 Protein*

Tong

Zhang

Buelow

et al. 2013

Journal of Biological Chemistry

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Background:The epigenetic mechanism underlying E4BP4-dependent repression of hepatic Fgf21 during refeeding is unknown. Results: E4BP4 interacts with G9a, and knockdown of G9a by shRNA abolishes suppression of Fgf21 by refeeding in vivo. Conclusion: G9a is a co-repressor required for E4BP4-dependent repression of Fgf21 expression. Significance: G9a is a critical histone methyltransferase in E4BP4-dependent repression of Fgf21 during refeeding.

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“…In the fed state, where ketogenesis is normally suppressed by insulin, the Fgf21 tg mice have increased ketogenesis compared with control mice (6). The Fgf21 knockout mice display mild obesity, hepatic steatosis, and glucose intolerance as well as impaired ketogenesis in response to fasting (3,8).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, a part of the fibroblast growth factor (FGF) family proteins have been described to be involved in the regulation of metabolic processes and function in an endocrine manner (2,3,4,5,6). These proteins include FGF19, 21, and 23 and are distinguished from the rest of the FGF proteins by lacking the heparin-binding domain, allowing them to diffuse away from their tissue of origin (7).…”

Section: Introductionmentioning

confidence: 99%

“…These proteins include FGF19, 21, and 23 and are distinguished from the rest of the FGF proteins by lacking the heparin-binding domain, allowing them to diffuse away from their tissue of origin (7). Pharmacologically, FGF21 has been shown to be a regulator of glucose and lipid metabolism in both rodents and primates (2,3,4,5,6). Transgenic (tg) mice overexpressing Fgf21 are resistant to diet-induced obesity, have a lower fasting blood glucose level, as well as improved glucose tolerance compared with their wild-type littermates (2).…”

Section: Introductionmentioning

confidence: 99%

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Impact of short-term high-fat feeding and insulin-stimulated FGF21 levels in subjects with low birth weight and controls

Vienberg

Brøns²,

Nilsson³

et al. 2012

European Journal of Endocrinology

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ObjectiveFibroblast growth factor 21 (FGF21) is a metabolic factor involved in glucose and lipid metabolism. However, little is known about the physiological role of FGF21 during a dietary challenge in humans.Research design and methodsTwenty healthy low birth weight (LBW) with known risk of type 2 diabetes and 26 control (normal birth weight (NBW)) young men were subjected to 5 days of high-fat (HF) overfeeding (+50%). Basal and clamp insulin-stimulated serum FGF21 levels were examined before and after the diet, andFGF21mRNA expression was measured in muscle and fat biopsies respectively.ResultsFive days of HF overfeeding diet significantly (P<0.001) increased fasting serum FGF21 levels in both the groups (P<0.001). Furthermore, insulin infusion additionally increased serum FGF21 levels to a similar extent in both the groups. Basal mRNA expression ofFGF21in muscle was near the detection limit and not present in fat in both the groups before and after the dietary challenge. However, insulin significantly (P<0.001) increasedFGF21mRNA in both muscle and fat in both the groups during both diets.ConclusionShort-term HF overfeeding markedly increased serum FGF21 levels in healthy young men with and without LBW but failed to increase muscle or fatFGF21mRNA levels. This suggests that the liver may be responsible for the rise of serum FGF21 levels during overfeeding. In contrast, the increase in serum FGF21 levels during insulin infusion may arise from increased transcription in muscle and fat. We speculate that increased serum FGF21 levels during HF overfeeding may be a compensatory response to increase fatty acid oxidation and energy expenditure.

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Fibroblast Growth Factor 21-Deficient Mice Demonstrate Impaired Adaptation to Ketosis

Cited by 321 publications

References 27 publications

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Thyroid Hormone Regulates Hepatic Expression of Fibroblast Growth Factor 21 in a PPARα-dependent Manner

Recruitment of Histone Methyltransferase G9a Mediates Transcriptional Repression of Fgf21 Gene by E4BP4 Protein*

Impact of short-term high-fat feeding and insulin-stimulated FGF21 levels in subjects with low birth weight and controls

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