Female adipose tissue-specific Bscl2 knockout mice develop only moderate metabolic dysfunction when housed at thermoneutrality and fed a high-fat diet

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Abstract

Mutations affecting the BSCL2 gene cause the most severe form of congenital generalised lipodystrophy. Affected individuals almost completely lack adipose tissue and suffer from severe diabetes and metabolic complications. Likewise, mice lacking Bscl2 in all tissues have dramatically reduced adipose mass, glucose intolerance and hyperinsulinaemia. However, male adipose tissue-specific Bscl2 knockout mice fail to develop the metabolic dysfunction observed in Bscl2 null mice and BSCL2 deficient patients, despite a similar generalised lack of adipose tissues. Clinical reports indicate gender differences frequently exist in cases of lipodystrophy, with female patients more adversely affected than male patients. We therefore generated and characterised female mice lacking Bscl2 specifically in adipose tissue (Ad-B2(−/−)). We show that female Ad-B2(−/−) mice also develop early-onset lipodystrophy when fed a chow diet and are maintained under standard housing conditions (21 °C) or thermoneutrality (30 °C). Despite this, female Ad-B2(−/−) mice fail to develop severe metabolic dysfunction. Only when female Ad-B2(−/−) mice are maintained at thermoneutrality and fed a high-fat diet do subtle alterations to metabolic homeostasis manifest. This is despite a striking inability to expand adipose mass. Our findings provide further evidence that loss of Bscl2 in non-adipose tissues may contribute to the severity of metabolic dysfunction in this condition.
Original languageEnglish
Article number17863
JournalScientific Reports
Volume8
DOIs
Publication statusPublished - 14 Dec 2018

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High Fat Diet
Knockout Mice
Adipose Tissue
Lipodystrophy
Congenital Generalized Lipodystrophy
Glucose Intolerance
Hyperinsulinism
Diabetes Complications
Homeostasis
Diet
Mutation
Genes

Keywords

  • fat metabolism
  • mechanisms of disease
  • mouse

Cite this

@article{bc3c6934964a4d3c9ab55dcd4f8acaf6,
title = "Female adipose tissue-specific Bscl2 knockout mice develop only moderate metabolic dysfunction when housed at thermoneutrality and fed a high-fat diet",
abstract = "Mutations affecting the BSCL2 gene cause the most severe form of congenital generalised lipodystrophy. Affected individuals almost completely lack adipose tissue and suffer from severe diabetes and metabolic complications. Likewise, mice lacking Bscl2 in all tissues have dramatically reduced adipose mass, glucose intolerance and hyperinsulinaemia. However, male adipose tissue-specific Bscl2 knockout mice fail to develop the metabolic dysfunction observed in Bscl2 null mice and BSCL2 deficient patients, despite a similar generalised lack of adipose tissues. Clinical reports indicate gender differences frequently exist in cases of lipodystrophy, with female patients more adversely affected than male patients. We therefore generated and characterised female mice lacking Bscl2 specifically in adipose tissue (Ad-B2(−/−)). We show that female Ad-B2(−/−) mice also develop early-onset lipodystrophy when fed a chow diet and are maintained under standard housing conditions (21 °C) or thermoneutrality (30 °C). Despite this, female Ad-B2(−/−) mice fail to develop severe metabolic dysfunction. Only when female Ad-B2(−/−) mice are maintained at thermoneutrality and fed a high-fat diet do subtle alterations to metabolic homeostasis manifest. This is despite a striking inability to expand adipose mass. Our findings provide further evidence that loss of Bscl2 in non-adipose tissues may contribute to the severity of metabolic dysfunction in this condition.",
keywords = "fat metabolism, mechanisms of disease, mouse",
author = "McIlroy, {George D} and Mitchell, {Sharon E} and Weiping Han and Mirela Delibegovic and Rochford, {Justin J}",
note = "The authors would like to thank the staff at the University of Aberdeen’s Medical Research Facility. We are very grateful for the gift of the Adiponectin-Cre mice from Dr. Evan Rosen (Beth Israel Deaconess Medical Centre and Harvard Medical School, Boston, USA). Work was supported by the Medical Research Council (GDM/JJR; MR/L002620/1, MC/PC/15077), the Biotechnology and Biological Sciences Research Council (JJR; BB/K017772/1), the British Heart Foundation (MD; PG/14/43/30889) and The Agency for Science, Technology and Research, Singapore (A*STAR) (WH). The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.",
year = "2018",
month = "12",
day = "14",
doi = "10.1038/s41598-018-36078-9",
language = "English",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
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T1 - Female adipose tissue-specific Bscl2 knockout mice develop only moderate metabolic dysfunction when housed at thermoneutrality and fed a high-fat diet

AU - McIlroy, George D

AU - Mitchell, Sharon E

AU - Han, Weiping

AU - Delibegovic, Mirela

AU - Rochford, Justin J

N1 - The authors would like to thank the staff at the University of Aberdeen’s Medical Research Facility. We are very grateful for the gift of the Adiponectin-Cre mice from Dr. Evan Rosen (Beth Israel Deaconess Medical Centre and Harvard Medical School, Boston, USA). Work was supported by the Medical Research Council (GDM/JJR; MR/L002620/1, MC/PC/15077), the Biotechnology and Biological Sciences Research Council (JJR; BB/K017772/1), the British Heart Foundation (MD; PG/14/43/30889) and The Agency for Science, Technology and Research, Singapore (A*STAR) (WH). The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

PY - 2018/12/14

Y1 - 2018/12/14

N2 - Mutations affecting the BSCL2 gene cause the most severe form of congenital generalised lipodystrophy. Affected individuals almost completely lack adipose tissue and suffer from severe diabetes and metabolic complications. Likewise, mice lacking Bscl2 in all tissues have dramatically reduced adipose mass, glucose intolerance and hyperinsulinaemia. However, male adipose tissue-specific Bscl2 knockout mice fail to develop the metabolic dysfunction observed in Bscl2 null mice and BSCL2 deficient patients, despite a similar generalised lack of adipose tissues. Clinical reports indicate gender differences frequently exist in cases of lipodystrophy, with female patients more adversely affected than male patients. We therefore generated and characterised female mice lacking Bscl2 specifically in adipose tissue (Ad-B2(−/−)). We show that female Ad-B2(−/−) mice also develop early-onset lipodystrophy when fed a chow diet and are maintained under standard housing conditions (21 °C) or thermoneutrality (30 °C). Despite this, female Ad-B2(−/−) mice fail to develop severe metabolic dysfunction. Only when female Ad-B2(−/−) mice are maintained at thermoneutrality and fed a high-fat diet do subtle alterations to metabolic homeostasis manifest. This is despite a striking inability to expand adipose mass. Our findings provide further evidence that loss of Bscl2 in non-adipose tissues may contribute to the severity of metabolic dysfunction in this condition.

AB - Mutations affecting the BSCL2 gene cause the most severe form of congenital generalised lipodystrophy. Affected individuals almost completely lack adipose tissue and suffer from severe diabetes and metabolic complications. Likewise, mice lacking Bscl2 in all tissues have dramatically reduced adipose mass, glucose intolerance and hyperinsulinaemia. However, male adipose tissue-specific Bscl2 knockout mice fail to develop the metabolic dysfunction observed in Bscl2 null mice and BSCL2 deficient patients, despite a similar generalised lack of adipose tissues. Clinical reports indicate gender differences frequently exist in cases of lipodystrophy, with female patients more adversely affected than male patients. We therefore generated and characterised female mice lacking Bscl2 specifically in adipose tissue (Ad-B2(−/−)). We show that female Ad-B2(−/−) mice also develop early-onset lipodystrophy when fed a chow diet and are maintained under standard housing conditions (21 °C) or thermoneutrality (30 °C). Despite this, female Ad-B2(−/−) mice fail to develop severe metabolic dysfunction. Only when female Ad-B2(−/−) mice are maintained at thermoneutrality and fed a high-fat diet do subtle alterations to metabolic homeostasis manifest. This is despite a striking inability to expand adipose mass. Our findings provide further evidence that loss of Bscl2 in non-adipose tissues may contribute to the severity of metabolic dysfunction in this condition.

KW - fat metabolism

KW - mechanisms of disease

KW - mouse

U2 - 10.1038/s41598-018-36078-9

DO - 10.1038/s41598-018-36078-9

M3 - Article

VL - 8

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 17863

ER -