Journal
DIABETES
Volume 70, Issue 9, Pages 1970-1984Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db20-1001
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Funding
- National Institutes of Health [T32 HD007505, T32 GM007863, F32 DK122654, R01 DK125513, R24 DK092759, R01 DK121759]
- National Institute of Diabetes and Digestive and Kidney Diseases [T32 DK101357, T32 DK071212, F32 DK123887]
- American Diabetes Association [1-18-PDF-064, 1-18-PDF-087]
- Michigan Life Sciences Fellows program
- Michigan Mouse Metabolic Phenotyping Center [U2C DK110768]
- Microscopy, Imaging, and Cellular Physiology Core [P30 DK020572]
- Adipose Tissue Core of the Michigan Nutrition Obesity Research Center [P30 DK089503]
- University of Michigan Advanced Genomics Core
- National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health [P30 AR069620]
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Using a mouse model with adipocyte-specific loss of Lmna, this study found that under high-fat diet conditions, the mice exhibit characteristics similar to FPLD2, including metabolic dysfunction and adipose tissue loss.
Mechanisms by which autosomal recessive mutations in Lmna cause familial partial lipodystrophy type 2 (FPLD2) are poorly understood. To investigate the function of lamin A/C in adipose tissue, we created mice with an adipocyte-specific loss of Lmna (Lmna(ADKO)). Although Lmna(ADKO) mice develop and maintain adipose tissues in early postnatal life, they show a striking and progressive loss of white and brown adipose tissues as they approach sexual maturity. Lmna(ADKO) mice exhibit surprisingly mild metabolic dysfunction on a chow diet, but on a high-fat diet they share many characteristics of FPLD2 including hyperglycemia, hepatic steatosis, hyperinsulinemia, and almost undetectable circulating adiponectin and leptin. Whereas Lmna(ADKO) mice have reduced regulated and constitutive bone marrow adipose tissue with a concomitant increase in cortical bone, FPLD2 patients have reduced bone mass and bone mineral density compared with controls. In cell culture models of Lmna deficiency, mesenchymal precursors undergo adipogenesis without impairment, whereas fully differentiated adipocytes have increased lipolytic responses to adrenergic stimuli. Lmna(ADKO) mice faithfully reproduce many characteristics of FPLD2 and thus provide a unique animal model to investigate mechanisms underlying Lmna-dependent loss of adipose tissues.
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