Direct effects of FGF21 on glucose uptake in human skeletal muscle: implications for type 2 diabetes and obesity

Mashili, Fredirick; Austin, Reginald L.; Deshmukh, Atul S.; Fritz, Tomas; Caidahl, Kenneth; Bergdahl, Katrin; Zierath, Juleen R.; Chibalin, Alexander V.; Moller, David E.; Kharitonenkov, Alexei; Krook, Anna

doi:10.1002/dmrr.1177

Cited by 194 publications

(159 citation statements)

References 104 publications

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“…Among them, FGF21 was overexpressed in the liver of LPTEN KO mice, resulting in elevated plasma FGF21 levels. This insulin-sensitizing hepatokine is of particular interest since it is known to enhance glucose uptake in muscle [22,23] and to increase energy expenditure in WAT [30]. Interestingly, FGF21 was also reported to stimulate UCP1 expression and browning of WAT [24,25], in accordance with our data.…”

Section: Discussionsupporting

confidence: 90%

“…4C, the expression of several hepatokines and cytokines, previously reported to modulate muscle insulin sensitivity and/ or WAT homeostasis, was significantly affected in the liver of LPTEN KO mice. Of particular interest, was the fibroblast growth factor 21 (FGF21), which has a positive effect on muscle insulin sensitivity and browning of adipose tissue [22][23][24][25]. Expression of Fgf21 was also strongly upregulated in isolated primary hepatocytes of LPTEN KO mice and plasma FGF21 levels mirrored the liver mRNA expression, altogether supporting a major hepatic origin of circulating FGF21 levels ( Fig.…”

Section: Hepatic Pten Deletion Decreases Lipid Storage In Fat Depotsmentioning

confidence: 88%

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Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice

Peyrou

Bourgoin

Poher

et al. 2015

Journal of Hepatology

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Background & Aims: PTEN is a dual lipid/protein phosphatase, downregulated in steatotic livers with obesity or HCV infection. Liver-specific PTEN knockout (LPTEN KO) mice develop steatosis, inflammation/fibrosis and hepatocellular carcinoma with aging, but surprisingly also enhanced glucose tolerance. This study aimed at understanding the mechanisms by which hepatic PTEN deficiency improves glucose tolerance, while promoting fatty liver diseases. Methods: Control and LPTEN KO mice underwent glucose/pyruvate tolerance tests and euglycemic-hyperinsulinemic clamps. Body fat distribution was assessed by EchoMRI, CT-scan and dissection analyses. Primary/cultured hepatocytes and insulin-sensitive tissues were analysed ex vivo. Results: PTEN deficiency in hepatocytes led to steatosis through increased fatty acid (FA) uptake and de novo lipogenesis. Although LPTEN KO mice exhibited hepatic steatosis, they displayed increased skeletal muscle insulin sensitivity and glucose uptake, as assessed by euglycemic-hyperinsulinemic clamps. Surprisingly, white adipose tissue (WAT) depots were also drastically reduced. Analyses of key enzymes involved in lipid metabolism further indicated that FA synthesis/esterification was decreased in WAT. In addition, Ucp1 expression and multilocular lipid droplet structures were observed in this tissue, indicating the presence of beige adipocytes. Consistent with a liver to muscle/ adipocyte crosstalk, the expression of liver-derived circulating factors, known to impact on muscle insulin sensitivity and WAT homeostasis (e.g. FGF21), was modulated in LPTEN KO mice.

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Section: Discussionsupporting

confidence: 90%

Section: Hepatic Pten Deletion Decreases Lipid Storage In Fat Depotsmentioning

confidence: 88%

Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice

Peyrou

Bourgoin

Poher

et al. 2015

Journal of Hepatology

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“…Like Hojman et al, we did not find a correlation between insulin-stimulated FGF21 mRNA expression and insulin-stimulated FGF21 serum levels, suggesting that the FGF21, produced by muscle and fat, may play a different role than FGF21 produced by liver and may function as a paracrine or even an autocrine factor. In agreement with this hypothesis, Mashili et al (38) recently showed that FGF21 increases insulinstimulated glucose uptake in human myotubes. However, it is interesting to notice that PPARGC1 expression is downregulated in the skeletal muscles after 5 days of HF overfeeding as previously shown in these subjects (26), despite the known stimulatory effect of FGF21 on PPARGC1 and lipid oxidation in at least liver (3) and adipose tissue (39).…”

Section: Discussionmentioning

confidence: 54%

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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“…As summarised in Table 1, in vitro studies have shown that IL-6 increases myotube fatty acid oxidation and lipolysis via AMPK activation [32,33]. [46] No data available regarding endocrine metabolic effects of muscle-derived BDNF IL-6 ↑ GLUT4 translocation [19,20] ↑ Glucose uptake [15,19] ↑ Glycogen synthesis [18,20] ↑ Fatty acid oxidation [18][19][20] ↑ Lipolysis [32][33][34] Liver: ↑ Glucose production [23] Intestine: ↑ GLP-1 secretion of L cells [52] Pancreas: ↑ Beta cell proliferation [52] ↑ GLP-1 secretion of alpha cells [52] ↑ Proliferation and ↓ apoptosis of alpha cells [51] IL-13 ↑ Glucose uptake [28] ↑ Glucose oxidation [28] ↑ Glycogen synthesis [28] Liver: ↓ Glucose production [29] IL-15 ↑ Fatty acid oxidation [43] Adipose tissue: ↓ Lipid accumulation [44,45] ↑ Adiponectin secretion [44] Irisin No data available Adipose tissue: ↑ White to brown shift [98,111] No effect on browning [100] FGF21 ↑ Glucose uptake [99,136] Adipose tissue: ↑ White to brown shift [99] ↑ Glucose uptake [99] ↑ Adiponectin secretion [127,128] Liver: ↑ Fatty acid oxidation [137] ↑ Gluconeogenesis [137] Recently, a study using isolated mouse muscle reported that IL-6...…”

Section: Myokines and Metabolic Regulationmentioning

confidence: 99%

Myokines in insulin resistance and type 2 diabetes

et al. 2014

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Skeletal muscle represents the largest organ of the body in non-obese individuals and is now considered to be an active endocrine organ releasing a host of so-called myokines. These myokines are part of a complex network that mediates communication between muscle, the liver, adipose tissue, the brain and other organs. Recent data suggest that myokines regulated by muscle contraction may play a key role in mediating the health-promoting effects of regular physical activity. Although hundreds of myokines have recently been described in proteomic studies, we currently have a rather limited knowledge of the specific role these myokines play in the prevention of insulin resistance, inflammation and associated metabolic dysfunction. Several myokines are known to have both local and endocrine functions, but in many cases the contribution of physical activity to the systemic level of these molecules remains as yet unexplored. Very recently, novel myokines such as irisin, which is thought to induce a white to brown shift in adipocytes, have gained considerable interest as potential therapeutic targets. In this review, we summarise the most recent findings on the role of myokines in the regulation of substrate metabolism and insulin sensitivity. We further explore the role of myokines in the regulation of inflammation and provide a critical assessment of irisin and other myokines regarding their potential as therapeutic targets.

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Direct effects of FGF21 on glucose uptake in human skeletal muscle: implications for type 2 diabetes and obesity

Cited by 194 publications

References 104 publications

Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice

Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice

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

Myokines in insulin resistance and type 2 diabetes

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