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Deletion of murine Arv1 results in a lean phenotype with increased energy expenditure.

Lagor WR, Tong F, Jarrett KE, Lin W, Conlon DM, Smith M, Wang MY, Yenilmez BO, McCoy MG, Fields DW, O'Neill SM, Gupta R, Kumaravel A, Redon V, Ahima RS, Sturley SL, Billheimer JT, Rader DJ - Nutr Diabetes (2015)

Bottom Line: Global loss of Arv1 significantly decreased total cholesterol and high-density lipoprotein cholesterol levels in the plasma.This loss of WAT is accompanied by improved glucose tolerance, higher adiponectin levels, increased energy expenditure and greater rates of whole-body FA oxidation.This work identifies Arv1 as an important player in mammalian lipid metabolism and whole-body energy homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.

ABSTRACT

Background: ACAT-related enzyme 2 required for viability 1 (ARV1) is a putative lipid transporter of the endoplasmic reticulum that is conserved across eukaryotic species. The ARV1 protein contains a conserved N-terminal cytosolic zinc ribbon motif known as the ARV1 homology domain, followed by multiple transmembrane regions anchoring it in the ER. Deletion of ARV1 in yeast results in defective sterol trafficking, aberrant lipid synthesis, ER stress, membrane disorganization and hypersensitivity to fatty acids (FAs). We sought to investigate the role of Arv1 in mammalian lipid metabolism.

Methods: Homologous recombination was used to disrupt the Arv1 gene in mice. Animals were examined for alterations in lipid and lipoprotein levels, body weight, body composition, glucose tolerance and energy expenditure.

Results: Global loss of Arv1 significantly decreased total cholesterol and high-density lipoprotein cholesterol levels in the plasma. Arv1 knockout mice exhibited a dramatic lean phenotype, with major reductions in white adipose tissue (WAT) mass and body weight on a chow diet. This loss of WAT is accompanied by improved glucose tolerance, higher adiponectin levels, increased energy expenditure and greater rates of whole-body FA oxidation.

Conclusions: This work identifies Arv1 as an important player in mammalian lipid metabolism and whole-body energy homeostasis.

No MeSH data available.


Related in: MedlinePlus

Arv1 knockout mice have increased energy expenditure. Metabolic parameters and activity were measured over a 24 h period in 4–6-month-old male WT (n=6) and Arv1 KO (n=5) mice on a chow diet. (a) Food consumption, (b) water intake, (c) activity, (d) oxygen consumption (VO2) normalized to lean mass, (e) carbon dioxide production (VCO2) normalized to lean mass and (f) calculated heat production normalized to lean mass are shown. All the values are reported as the mean±s.d. (*P<0.05).
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fig5: Arv1 knockout mice have increased energy expenditure. Metabolic parameters and activity were measured over a 24 h period in 4–6-month-old male WT (n=6) and Arv1 KO (n=5) mice on a chow diet. (a) Food consumption, (b) water intake, (c) activity, (d) oxygen consumption (VO2) normalized to lean mass, (e) carbon dioxide production (VCO2) normalized to lean mass and (f) calculated heat production normalized to lean mass are shown. All the values are reported as the mean±s.d. (*P<0.05).

Mentions: The Arv1 KO mice were examined using metabolic cages to investigate the basis for the decreased fat mass and body weight. Arv1 KO mice consumed more food during the light cycle than WT mice (Figure 5a). No differences were observed in water intake (Figure 5b). Consistent with the increase in food consumption during the light hours, Arv1 KO mice were also more active during the light period than WT animals (Figure 5c). As expected based on the reduced WAT mass, we found that Arv1 KO animals did have increased oxygen consumption (VO2) and carbon dioxide production (VCO2), which reached statistical significance during the light hours (Figures 5d and e). The respiratory exchange ratio (RER) did not vary by genotype in the light phase, and the KO was only modestly lower than WT in the dark phase (WT: 0.905±0.025 versus KO 0.864±0.019, −4.5%, P<0.05), suggesting there was no major shift in carbohydrate versus fat utilization. Arv1 KO mice also expended more energy (calculated heat) than WT controls during the light cycle (Figure 5f). We hypothesized that the lack of TG stores in the WAT may be related to increased FA clearance and disposal. To test this, we measured fat tolerance in female Arv1 KO mice after an oral bolus of olive oil. Arv1 KO mice started out with a lower basal plasma TG level following an overnight fast, and had a nearly flat TG excursion after the olive oil gavage (Figure 6a). To test whether an increased rate of FA disposal could explain the difference in oral fat tolerance, we measured whole-body oxidation of a [3H]-oleic acid tracer. Consistent with the increase in energy expenditure, Arv1 KO mice also showed a robust 66% elevation in the rate of FA oxidation (Figure 6b).


Deletion of murine Arv1 results in a lean phenotype with increased energy expenditure.

Lagor WR, Tong F, Jarrett KE, Lin W, Conlon DM, Smith M, Wang MY, Yenilmez BO, McCoy MG, Fields DW, O'Neill SM, Gupta R, Kumaravel A, Redon V, Ahima RS, Sturley SL, Billheimer JT, Rader DJ - Nutr Diabetes (2015)

Arv1 knockout mice have increased energy expenditure. Metabolic parameters and activity were measured over a 24 h period in 4–6-month-old male WT (n=6) and Arv1 KO (n=5) mice on a chow diet. (a) Food consumption, (b) water intake, (c) activity, (d) oxygen consumption (VO2) normalized to lean mass, (e) carbon dioxide production (VCO2) normalized to lean mass and (f) calculated heat production normalized to lean mass are shown. All the values are reported as the mean±s.d. (*P<0.05).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4631934&req=5

fig5: Arv1 knockout mice have increased energy expenditure. Metabolic parameters and activity were measured over a 24 h period in 4–6-month-old male WT (n=6) and Arv1 KO (n=5) mice on a chow diet. (a) Food consumption, (b) water intake, (c) activity, (d) oxygen consumption (VO2) normalized to lean mass, (e) carbon dioxide production (VCO2) normalized to lean mass and (f) calculated heat production normalized to lean mass are shown. All the values are reported as the mean±s.d. (*P<0.05).
Mentions: The Arv1 KO mice were examined using metabolic cages to investigate the basis for the decreased fat mass and body weight. Arv1 KO mice consumed more food during the light cycle than WT mice (Figure 5a). No differences were observed in water intake (Figure 5b). Consistent with the increase in food consumption during the light hours, Arv1 KO mice were also more active during the light period than WT animals (Figure 5c). As expected based on the reduced WAT mass, we found that Arv1 KO animals did have increased oxygen consumption (VO2) and carbon dioxide production (VCO2), which reached statistical significance during the light hours (Figures 5d and e). The respiratory exchange ratio (RER) did not vary by genotype in the light phase, and the KO was only modestly lower than WT in the dark phase (WT: 0.905±0.025 versus KO 0.864±0.019, −4.5%, P<0.05), suggesting there was no major shift in carbohydrate versus fat utilization. Arv1 KO mice also expended more energy (calculated heat) than WT controls during the light cycle (Figure 5f). We hypothesized that the lack of TG stores in the WAT may be related to increased FA clearance and disposal. To test this, we measured fat tolerance in female Arv1 KO mice after an oral bolus of olive oil. Arv1 KO mice started out with a lower basal plasma TG level following an overnight fast, and had a nearly flat TG excursion after the olive oil gavage (Figure 6a). To test whether an increased rate of FA disposal could explain the difference in oral fat tolerance, we measured whole-body oxidation of a [3H]-oleic acid tracer. Consistent with the increase in energy expenditure, Arv1 KO mice also showed a robust 66% elevation in the rate of FA oxidation (Figure 6b).

Bottom Line: Global loss of Arv1 significantly decreased total cholesterol and high-density lipoprotein cholesterol levels in the plasma.This loss of WAT is accompanied by improved glucose tolerance, higher adiponectin levels, increased energy expenditure and greater rates of whole-body FA oxidation.This work identifies Arv1 as an important player in mammalian lipid metabolism and whole-body energy homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.

ABSTRACT

Background: ACAT-related enzyme 2 required for viability 1 (ARV1) is a putative lipid transporter of the endoplasmic reticulum that is conserved across eukaryotic species. The ARV1 protein contains a conserved N-terminal cytosolic zinc ribbon motif known as the ARV1 homology domain, followed by multiple transmembrane regions anchoring it in the ER. Deletion of ARV1 in yeast results in defective sterol trafficking, aberrant lipid synthesis, ER stress, membrane disorganization and hypersensitivity to fatty acids (FAs). We sought to investigate the role of Arv1 in mammalian lipid metabolism.

Methods: Homologous recombination was used to disrupt the Arv1 gene in mice. Animals were examined for alterations in lipid and lipoprotein levels, body weight, body composition, glucose tolerance and energy expenditure.

Results: Global loss of Arv1 significantly decreased total cholesterol and high-density lipoprotein cholesterol levels in the plasma. Arv1 knockout mice exhibited a dramatic lean phenotype, with major reductions in white adipose tissue (WAT) mass and body weight on a chow diet. This loss of WAT is accompanied by improved glucose tolerance, higher adiponectin levels, increased energy expenditure and greater rates of whole-body FA oxidation.

Conclusions: This work identifies Arv1 as an important player in mammalian lipid metabolism and whole-body energy homeostasis.

No MeSH data available.


Related in: MedlinePlus