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Deletion of Alzheimer's Disease Risk Gene ABCA7 Alters White Adipose Tissue Development and Leptin Levels.

ABSTRACT: ATP-binding cassette A7 (ABCA7) is a genetic risk factor for late-onset Alzheimer's disease (AD). It belongs to a group of transporter genes that specializes in regulating lipid transport in the periphery as well as in the brain. ABCA7 has been implicated in a number of roles relating to AD pathology, including phagocytic clearance of amyloid-? peptides. We have discovered that deletion of ABCA7 in mouse causes a dramatic reduction in white adipose tissue (WAT) in female mice. WAT is important in AD context because it is the primary producer of leptin, which is a hormone that is known to modulate AD neuropathology. WAT in male Abca7-/- mice was not altered. The pathological link between ABCA7 and WAT that impacts on AD is unknown. Our transcription analysis revealed that lipin-1 expression was significantly upregulated in female Abca7-/- mice, indicating that ABCA7 affects WAT development. The circulating leptin level was significantly reduced in female Abca7-/- mice without any change in WAT leptin mRNA or protein expression, indicating that ABCA7 does not affect leptin production, but alters the circulating leptin level indirectly by affecting WAT development. Insulin is a key hormone that regulates WAT development, i.e., adipogenesis, and it was significantly reduced in female Abca7-/- mice. These data when put together suggest that ABCA7 plays a role in regulating WAT development and consequently circulating leptin levels, which are known to modulate AD neuropathology.

SUBMITTER: Bhatia S

PROVIDER: S-EPMC6159609 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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Deletion of Alzheimer's Disease Risk Gene ABCA7 Alters White Adipose Tissue Development and Leptin Levels.

Bhatia Surabhi S Fu YuHong Y Hsiao Jen-Hsiang T JT Halliday Glenda M GM Kim Woojin Scott WS

Journal of Alzheimer's disease reports 20171216 1

ATP-binding cassette A7 (ABCA7) is a genetic risk factor for late-onset Alzheimer's disease (AD). It belongs to a group of transporter genes that specializes in regulating lipid transport in the periphery as well as in the brain. ABCA7 has been implicated in a number of roles relating to AD pathology, including phagocytic clearance of amyloid-β peptides. We have discovered that deletion of ABCA7 in mouse causes a dramatic reduction in white adipose tissue (WAT) in female mice. WAT is important i ...[more]

PMID: 30480241

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Project description:ObjectiveZfp423 is a multi zinc-finger transcription factor expressed in preadipocytes and mature adipocytes in vivo. Our recent work has revealed a critical role for Zfp423 in maintaining the fate of white adipocytes in adult mice through suppression of the beige cell thermogenic gene program; loss of Zfp423 in mature adipocytes of adult mice results in a white-to-beige phenotypic switch. However, the exact requirements of Zfp423 in the fetal stages of early adipose development in vivo have not been clarified.MethodHere, we utilize two models that confer adipose-specific Zfp423 inactivation during fetal adipose development (Adiponectin-Cre; Zfp423loxP/loxP and Adiponectin-rtTA; TRE-Cre; Zfp423loxP/loxP). We assess the impact of fetal adipose Zfp423 deletion on the initial formation of adipose tissue and evaluate the metabolic consequences of challenging these animals with high-fat diet feeding.ResultsDeletion of Zfp423 during fetal adipose development results in a different phenotype than is observed when deleting Zfp423 in adipocytes of adult mice. Inactivation of Zfp423 during fetal adipose development results in arrested differentiation, specifically of inguinal white adipocytes, rather than a white-to-beige phenotypic switch that occurs when Zfp423 is inactivated in adult mice. This is likely explained by the observation that adiponectin driven Cre expression is active at an earlier stage of the adipocyte life cycle during fetal subcutaneous adipose development than in adult mice. Upon high-fat diet feeding, obese adipose Zfp423-deficient animals undergo a pathological adipose tissue expansion, associated with ectopic lipid deposition and systemic insulin resistance.ConclusionsOur results reveal that Zfp423 is essential for the terminal differentiation of subcutaneous white adipocytes during fetal adipose tissue development. Moreover, our data highlight the striking adverse effects of pathological subcutaneous adipose tissue remodeling on visceral adipose function and systemic nutrient homeostasis in obesity. Importantly, these data reveal the distinct phenotypes that can occur when adiponectin driven transgenes are activated in fetal vs. adult adipose tissue.

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Deletion of Alzheimer's Disease Risk Gene ABCA7 Alters White Adipose Tissue Development and Leptin Levels.

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Deletion of Alzheimer's Disease Risk Gene ABCA7 Alters White Adipose Tissue Development and Leptin Levels.

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