Ultrastructure of the liver microcirculation influences hepatic and systemic insulin activity and provides a mechanism for age-related insulin resistance.
While age-related insulin resistance and hyperinsulinemia are usually considered to be secondary to changes in muscle, the liver also plays a key role in whole-body insulin handling and its role in age-related changes in insulin homeostasis is largely unknown. Here, we show that patent pores called 'fenestrations' are essential for insulin transfer across the liver sinusoidal endothelium and that age-related loss of fenestrations causes an impaired insulin clearance and hyperinsulinemia, induces hepatic insulin resistance, impairs hepatic insulin signaling, and deranges glucose homeostasis. To further define the role of fenestrations in hepatic insulin signaling without any of the long-term adaptive responses that occur with aging, we induced acute defenestration using poloxamer 407 (P407), and this replicated many of the age-related changes in hepatic glucose and insulin handling. Loss of fenestrations in the liver sinusoidal endothelium is a hallmark of aging that has previously been shown to cause deficits in hepatic drug and lipoprotein metabolism and now insulin. Liver defenestration thus provides a new mechanism that potentially contributes to age-related insulin resistance.
Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, University of Sydney and Concord Hospital, Sydney, NSW, Australia.|ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, NSW, Australia.|Faculty of Pharmacy, Universiti Teknologi MARA, Selangor, Malaysia.
Mashani
M
Mohamad
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Sarah Jayne
SJ
Mitchell
Laboratory for Ageing Research, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Lindsay Edward
LE
Wu
Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.
Melanie Yvonne
MY
White
Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.
Stuart James
SJ
Cordwell
Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney, NSW, Australia.
John
J
Mach
Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, University of Sydney and Concord Hospital, Sydney, NSW, Australia.|ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, NSW, Australia.|Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.
Samantha Marie
SM
Solon-Biet
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Dawn
D
Boyer
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Dawn
D
Nines
Laboratory for Ageing Research, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Abhirup
A
Das
Laboratory for Ageing Research, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
Shi-Yun
SY
Catherine Li
Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, University of Sydney and Concord Hospital, Sydney, NSW, Australia.|ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, NSW, Australia.
Alessandra
A
Warren
Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney, NSW, Australia.
Sarah Nicole
SN
Hilmer
Department of Pathology, University of Otago, Christchurch, New Zealand.
Robin
R
Fraser
Laboratory for Ageing Research, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.|Department of Genetics, Harvard Medical School, Boston, MA, USA.
David Andrew
DA
Sinclair
Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.
Stephen James
SJ
Simpson
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Rafael
R
de Cabo
Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, University of Sydney and Concord Hospital, Sydney, NSW, Australia.|ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, NSW, Australia.|Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.
David George
DG
Le Couteur
Ageing and Alzheimers Institute, Centre for Education and Research on Ageing, University of Sydney and Concord Hospital, Sydney, NSW, Australia.|ANZAC Research Institute, University of Sydney and Concord Hospital, Sydney, NSW, Australia.|Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia.
Victoria Carroll
VC
Cogger
D000375:Aging / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure*; D008297:Male; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D020442:Poloxamer; D016062:Porosity; D011916:Rats, Inbred F344; D013194:Staining and Labeling
D007328:Insulin; D020442:Poloxamer; D006003:Glycogen; D005947:Glucose
ageing; aging; endothelium; fenestrae; fenestrations; hyperinsulinemia