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. 2015 Aug;64(8):2757-68.
doi: 10.2337/db14-1035. Epub 2015 Mar 31.

Perilipin 5-Driven Lipid Droplet Accumulation in Skeletal Muscle Stimulates the Expression of Fibroblast Growth Factor 21

Lydia-Ann L S Harris  1 , James R Skinner  1 , Trevor M Shew  1 , Terri A Pietka  1 , Nada A Abumrad  2 , Nathan E Wolins  3
Affiliations

Perilipin 5-Driven Lipid Droplet Accumulation in Skeletal Muscle Stimulates the Expression of Fibroblast Growth Factor 21

Lydia-Ann L S Harris et al. Diabetes. 2015 Aug.

Abstract

Perilipin 5 (PLIN5) is a lipid droplet protein and is highly expressed in oxidative tissue. Expression of the PLIN5 gene is regulated by peroxisome proliferator-activated receptor-α, fasting, and exercise. However, the effect of increased muscle PLIN5 expression on whole-body energy homeostasis remains unclear. To examine this, we developed a mouse line with skeletal muscle PLIN5 overexpression (MCK-Plin5). We show that MCK-Plin5 mice have increased energy metabolism and accumulate more intramyocellular triacylglycerol but have normal glucose and insulin tolerance. MCK-Plin5 mice fed high-fat chow manifest lower expression of inflammatory markers in their liver and increased expression of "browning" factors in adipose tissue. This muscle-driven phenotype is, at least in part, mediated by myokines; the MCK-Plin5 mice have 80-fold higher FGF21 gene expression in muscle and increased serum FGF21 concentration. The increase in FGF21 occurs mainly in muscles with a predominance of fast-twitch fibers, suggesting that fiber type-specific lipid storage may be part of the mechanism conferring metabolic protection in MCK-Plin5 mice. In conclusion, upregulating the PLIN5 level in skeletal muscle drives expression of the FGF21 gene in fast-twitch fibers and is metabolically protective. These findings provide insight into the physiology of PLIN5 and the potential contribution of its upregulation during exercise.

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Figures

Figure 1
Figure 1
MCK-Plin5 mice have increased LDs and intramyocellular TAG. A: Top: Hindquarters of a control NTG and MCK-Plin5 mouse showing the difference in muscle color. Bottom: Western blot of gastrocnemius showing PLIN5 levels. B: PLIN5 mRNA expression in the heart, soleus (Sol), diaphragm (Dia), EDL, and gastrocnemius (Gn); expression was normalized to that of the housekeeping gene 36B4 (represented as arbitrary units [AUs]). C: Micrographs of collagenase-isolated gastrocnemius myofibrils with LDs stained with BODIPY 493/503 fluorochrome (green) and nuclei stained with DAPI (blue). D: Micrograph of an isolated gastrocnemius fiber. LDs are stained with BODIPY 493/503 fluorochrome (red), PLIN5 is labeled with anti-PLIN5 antibody (green), and nuclei are stained with DAPI (blue). The arrow points to a PLIN5-coated LD. E: Quantification of TAG content in the heart, Sol, Dia, EDL, and Gn (n = 10 mice per group). TAG levels in MCK-Plin5 muscle are expressed relative to that of NTG muscle. F: Mass spectrometry assessment of ceramide (CER), DAG, and TAG in gastrocnemius muscle (NTG mice, n = 4; MCK-Plin5 mice, n = 7). *P < 0.05; **P < 0.01. The data shown are representative of at least two experiments.
Figure 2
Figure 2
MCK-Plin5 mice gain less weight on a standard chow diet and have increased carbohydrate metabolism. A: Weight of mice on a chow diet. Mice were weighed weekly for 9 weeks (NTG mice, n = 16; MCK-Plin5 mice, n = 22). The data shown are representative of at least two experiments. B: Lean and fat mass expressed as a percentage of body weight (n = 4 mice per group). C–E: Energy expenditure (C), RER (D), and activity (E) during light and dark periods. Energy expenditure and activity were measured simultaneously (NTG mice, n = 5; MCK-Plin5 mice, n = 6). F: Glucose tolerance and insulin sensitivity (n = 10 mice per group). *P < 0.05.
Figure 3
Figure 3
MCK-Plin5 mice have normal muscle function. A: Electron micrograph of the gastrocnemius fibers of an NTG (left) and MCK-Plin5 (right) mouse showing that mitochondria surround interfibrillar LDs in the transgenic muscle. Arrow heads show mitochondria and arrows show LDs. The data are representative of at least two experiments. B: Exercise endurance in NTG and MCK-Plin5 mice in the fed or fasted (16 h) state (n = 4 mice per group). C: Evaluation of O2 consumption by the EDL in the presence of various substrates: malate, glutamate, ADP (GMD; complex I); malate, glutamate, ADP, succinate (GMDS; complex II); FCCP (uncoupled respiration); rotenone (ROT; complex I inhibition); and antimycin A (AA; nonmitochondria respiration) (NTG mice, n = 5; MCK-Plin5 mice, n = 6). D: Western blot showing the various mitochondrial protein complexes: complex I (C I), complex II (C II), complex III (C III), complex IV (C IV), complex V (C V), and Ras-related nuclear protein (RAN). E: Quantification of Western (n = 8 per group) signals normalized to that of RAN and compared with control. F: mRNA expression of Atf3 and Atf4 genes in the gastrocnemius. *P < 0.05. G: mRNA expression of ATF4 target genes in the gastrocnemius (n = 10 per group). **P < 0.01. AU, arbitrary unit.
Figure 4
Figure 4
PLIN5 overexpression in muscle protects the liver in mice fed an HF diet. A: Weights of mice on an HF diet. Mice were weighed weekly for 9 weeks (NTG mice, n = 17; MCK-Plin5 mice, n = 14). B: Lean and fat mass as a percentage of body weight (NTG mice, n = 4; MCK-Plin5 mice, n = 7). C: Glucose tolerance. D: Insulin sensitivity. The data shown are representative of two separate experiments. E: Liver weights, liver cholesterol, NEFA, and TAG. Liver weight is expressed as a percentage of body weight (BW), and lipid content is normalized to milligrams protein. F: Quantitative RT-PCR data showing gene expression of lipid transport and metabolism genes (left) and markers of inflammation in the livers of mice fed an HF diet (right) (NTG mice, n = 10; MCK-Plin5 mice, n = 9). *P < 0.05; **P < 0.01. IL, interleukin; n.s., not significant; TNF, tumor necrosis factor.
Figure 5
Figure 5
PLIN5 overexpression increases FGF21 expression in gastrocnemius and EDL muscles and increases FGF21 serum concentrations. A: mRNA expression of interleukin (Il)-6, chemokine (C-X-C motif) ligand (Cxcl) 1 and 2, fibronectin type III domain containing 5 (Fndc), and leukemia inhibitory factor (Lif) in the gastrocnemius. B: FGF21 mRNA expression in the heart, soleus (Sol), diaphragm (Dia), EDL, gastrocnemius (Gn), liver, and epididymal WAT (E-WAT) of mice fed standard chow. C: FGF21 mRNA expression in the Gn, liver, and E-WAT of mice fed a high-fat diet. D: Fasting serum FGF21 in mice receiving standard (S) and HF chow. E: Serum FGF21 in nonfasting (basal) chow-fed mice (NTG mice, n = 4; MCK-Plin5 mice, n = 6). F: mRNA expression of “browning” factors in the E-WAT (NTG mice, n = 10; MCK-Plin5 mice, n = 9). Except where indicated, measurements were obtained from mice fasted overnight. *P < 0.05; **P < 0.01. AU, arbitrary unit.
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