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Administration of alpha klotho reduces liver and adipose lipid accumulation in obese mice.

ABSTRACT: ?-Klotho, a known anti-aging protein, exerts diverse physiological effects including: maintenance of phosphate and calcium homeostasis, modulation of cell proliferation, and enhanced buffering of reactive oxygen species. However, the role of ?-Klotho in the regulation of energy metabolism is complex and poorly understood. Here we investigated the effects of 5 weeks peripheral administration of ?-Klotho in high fat diet induced obese mice. Food intake, blood glucose, and body weight were measured daily. Energy expenditure was determined with indirect calorimetry and body composition with magnetic resonance imaging. Liver and adipose tissue were collected for lipid content measurements and gene expression analysis. ?-Klotho-treated mice experienced reduced adiposity, increased lean mass, and elevated energy expenditure, despite no changes in food intake, body weight, or fed blood glucose levels. Lipid accumulation in liver and adipose tissue was also reduced compared to controls. Furthermore, Real-time quantitative PCR showed reduced expression of key lipogenic genes in ?-Klotho treated mice in these organs. Taken together, these data suggest encouraging therapeutic potential of ?-Klotho and highlight a need for further research into the specific mechanisms explaining improved body composition, elevated energy expenditure, and reduced lipid content in both liver and adipose tissue in ?-Klotho-treated mice.

SUBMITTER: Rao Z

PROVIDER: S-EPMC6484204 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Administration of alpha klotho reduces liver and adipose lipid accumulation in obese mice.

Rao Zhijian Z Landry Taylor T Li Peixin P Bunner Wyatt W Laing Brenton Thomas BT Yuan Yuan Y Huang Hu H

Heliyon 20190424 4

α-Klotho, a known anti-aging protein, exerts diverse physiological effects including: maintenance of phosphate and calcium homeostasis, modulation of cell proliferation, and enhanced buffering of reactive oxygen species. However, the role of α-Klotho in the regulation of energy metabolism is complex and poorly understood. Here we investigated the effects of 5 weeks peripheral administration of α-Klotho in high fat diet induced obese mice. Food intake, blood glucose, and body weight were measured ...[more]

PMID: 31049427

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Project description:BackgroundObesity is associated with extensive white adipose tissue (WAT) expansion and remodeling. Healthy WAT expansion contributes to the maintenance of energy balance in the liver, thereby ameliorating obesity-related hepatic steatosis. Tissue-resident mesenchymal stromal cell populations, including PDGFRβ + perivascular cells, are increasingly recognized pivotal as determinants of the manner in which WAT expands. However, the full array of regulatory factors controlling WAT stromal cell functions remains to be fully elucidated. Hypoxia-inducible factors (HIFs) are critical regulators in WAT stromal cell populations such as adipocyte precursor cells (APCs). It is revealed that HIF1α activation within PDGFRβ + stromal cells results in the suppression of de novo adipogenesis and the promotion of a pro-fibrogenic cellular program in obese animals. However, the role of HIF2α in PDGFRβ + cells remains undetermined in vivo.MethodsNew genetic models were employed in which HIF1α (encoded by the Hif1a gene) and HIF2α (encoded by the Epas1 gene) are selectively inactivated in PDGFRβ + cells in an inducible manner using tamoxifen (TAM). With these models, both in vitro and in vivo functional analysis of PDGFRβ + cells lacking HIF proteins were performed. Additionally, comprehensive metabolic phenotyping in diet-induced mouse models were performed to investigate the roles of PDGFRβ + cell HIF proteins in WAT remodeling, liver energy balance and systemic metabolism.ResultsUnlike HIF1α inactivation, the new findings in this study suggest that inducible ablation of HIF2α in PDGFRβ + cells does not cause apparent effects on WAT expansion induced by obesogenic diet. The adipogenic ability of PDGFRβ + APCs is not significantly altered by genetic HIF2α ablation. Moreover, no difference of key parameters associated with healthy WAT remodeling such as improvements of WAT insulin sensitivity, reduction in metabolic inflammation, as well as changes in liver fat accumulation or systemic glucose metabolism, is detected in PDGFRβ + cell Epas1-deficient mice.ConclusionThe new findings in this study support that, in contrast to HIF1α, PDGFRβ + cell HIF2α appears dispensable for WAT metabolic remodeling and the resulting effects on liver metabolic homeostasis in diet-induced obesity, underscoring the isoform-specific roles of HIFα proteins in the regulation of adipose tissue biology.

Dataset Information

Administration of alpha klotho reduces liver and adipose lipid accumulation in obese mice.

Publications

Administration of alpha klotho reduces liver and adipose lipid accumulation in obese mice.

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