Endocrinol Metab.  2021 Jun;36(3):661-671. 10.3803/EnM.2021.1023.

Expression of LONP1 Is High in Visceral Adipose Tissue in Obesity, and Is Associated with Glucose and Lipid Metabolism

• Lee JH
• Jung SB
• Lee SE
• Kim JE
• Kim JT
• Kang YE
• Kang SG
• Yi HS
• Ko YB
• Lee KH
• Ku BJ
• Shong M
• Kim HJ

• KMID: 2517656
• DOI: http://doi.org/10.3803/EnM.2021.1023

Abstract

Background
The nature and role of the mitochondrial stress response in adipose tissue in relation to obesity are not yet known. To determine whether the mitochondrial unfolded protein response (UPR^mt) in adipose tissue is associated with obesity in humans and rodents.
Methods
Visceral adipose tissue (VAT) was obtained from 48 normoglycemic women who underwent surgery. Expression levels of mRNA and proteins were measured for mitochondrial chaperones, intrinsic proteases, and components of electron-transport chains. Furthermore, we systematically analyzed metabolic phenotypes with a large panel of isogenic BXD inbred mouse strains and Genotype-Tissue Expression (GTEx) data.
Results
In VAT, expression of mitochondrial chaperones and intrinsic proteases localized in inner and outer mitochondrial membranes was not associated with body mass index (BMI), except for the Lon protease homolog, mitochondrial, and the corresponding gene LONP1, which showed high-level expression in the VAT of overweight or obese individuals. Expression of LONP1 in VAT positively correlated with BMI. Analysis of the GTEx database revealed that elevation of LONP1 expression is associated with enhancement of genes involved in glucose and lipid metabolism in VAT. Mice with higher Lonp1 expression in adipose tissue had better systemic glucose metabolism than mice with lower Lonp1 expression.
Conclusion
Expression of mitochondrial LONP1, which is involved in the mitochondrial quality control stress response, was elevated in the VAT of obese individuals. In a bioinformatics analysis, high LONP1 expression in VAT was associated with enhanced glucose and lipid metabolism.

Keyword

Intra-abdominal fat; Obesity; Metabolic syndrome

Figure

• 

  Fig. 1 Visceral adipose tissue expression of genes encoding proteins of the oxidative phosphorylation (OXPHOS) complex, mitochondrial chaperones, and proteases in relation to body mass index (BMI). Relative mRNA expression of genes of the OXPHOS complex (A) and mitochondrial biogenesis (B) in the visceral adipose tissue between a group with BMI <23 kg/m2 (n=26) and a group with BMI ≥23 kg/m2 (n=26). Gene expression relative to the mean level in the group with BMI <23 kg/m2 was determined for each sample by real-time polymerase chain reaction. (C) Relative mitochondrial DNA (mtDNA) content. (D) Malondianldehyde concentration. (E) Relative mRNA expression of genes encoding mitochondrial chaperones and proteases. (F) Correlation between Lon peptidase 1, mitochondrial (LONP1) mRNA expression in the visceral adipose tissue and BMI. Relative mRNA expression is presented as mean±standard error of the mean. P values were calculated by the Mann-Whitney U test. NDUFA9, NADH:ubiquinone oxidoreductase subunit A9; SDHB, NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8, mitochondrial; UQCRC2, ubiquinol-cytochrome-c reductase complex core protein 2; COX2, cytochrome c oxidase subunit II; ATP5A1A, ATP synthase F1 subunit alpha; PPARGC1A, PPARG coactivator 1 alpha; TFAM, transcription factor A, mitochondrial; HSPD1, heat shock protein family D (Hsp60) member 1; DNAJA3, DnaJ heat shock protein family (Hsp40) member A3; CLPP, caseinolytic mitochondrial matrix peptidase proteolytic subunit; YME1L1, YME1 like 1 ATPase; HTRA2, HtrA serine peptidase 2; USP30, ubiquitin specific peptidase 30. aP<0.01.

• 

  Fig. 2 Expression of proteins of the oxidative phosphorylation (OXPHOS) complex, transcription factors, mitochondrial chaperones, and proteases in human visceral adipose tissue. (A) Expression of mitochondrial chaperones and proteases in visceral adipose tissue of the five participants with the lowest body mass index (BMI; low BMI: mean, 18.6 kg/m2; range, 17.4 to 19.3 kg/m2) and the five with the highest BMI (high BMI: mean, 29.6 kg/m2; range, 27.5 to 31.8 kg/m2). (B) Expression of proteins of the OXPHOS complex. (C) Expression of transcription factor A, mitochondrial (TFAM). Western blot band density relative to β-actin of each sample is calculated and presented as mean±standard error of the mean (n=5). P values were calculated by the Mann-Whitney U test. HSPD1, 60 kDa heat shock protein, mitochondrial; DNAJA3, DnaJ heat shock protein family (Hsp40) member A3; CLPP, caseinolytic mitochondrial matrix peptidase proteolytic subunit; LONP1, Lon protease homolog, mitochondrial; NDUFB8, NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8, mitochondrial (OXPHOS complex I); SDHB, succinate dehydrogenase (ubiquinone) iron-sulfur subunit, mitochondrial (OXPHOS complex II); UQCRC2, ubiquinol-cytochrome-c reductase complex core protein 2 (OXPHOS complex III); COX1, cytochrome c oxidase subunit 1 (OXPHOS complex IV); ATP5A1A, ATP synthase F1 subunit alpha (OXPHOS complex V). aP<0.01; bP<0.001.

• 

  Fig. 3 Upregulation of physiological pathways in visceral adipose tissue with high expression of Lon protease homolog, mitochondrial (LONP1) in the Genotype-Tissue Expression Database. (A) LONP1 expression levels in 541 human visceral adipose tissue samples in the UCSC database. (B) Numbers of differentially expressed genes in a comparison of the samples in the highest quartile for LONP1 expression (n=134) and those in the lowest quartile (n=134). (C) Association of differential LONP1 expression with Gene Ontology (GO) biological processes (GO-BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. (D, E, F, G) Upregulated biological processes in the GO annotation or KEGG pathway analysis. TPM, transcripts per million.

• 

  Fig. 4 Metabolic phenotypes in BXD mouse strains in relation to Lon protease homolog, mitochondrial (Lonp1) expression. (A) Lonp1 expression level in the subcutaneous white adipose tissue (sWAT) according to diet. (B) Comparison of lowest quartile (Lonp1-low) and highest quartile (Lonp1-high) of Lonp1 expression levels in the sWAT of BXD mouse strains with chow diet (CD). (C) Body weight change in BXD mice fed CD. Blood glucose (D) and insulin (E) were measured during the oral glucose-tolerance test (OGTT) in male mice at 17 weeks of age receiving CD. (F) Comparison of lowest quartile (Lonp1-low high-fat diet [HFD]) and highest quartile (Lonp1-high-HFD) of Lonp1 expression levels in the sWAT of BXD mouse strains with HFD. (G) Body weight change in BXD mice fed a HFD. Blood glucose (H) and insulin (I) measured during OGTT in male mice at 17 weeks of age receiving HFD. P values were calculated by t test. aP<0.001; bP<0.05.

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