TY - JOUR
T1 - Antidiabetic E4orf1 protein prevents hepatic steatosis and reduces markers of aging-related cellular damage in high fat fed older mice
AU - Mostofinejad, Zahra
AU - Akheruzzaman, Md
AU - Abu Bakkar Siddik, Md
AU - Patkar, Presheet
AU - Dhurandhar, Nikhil V.
AU - Hegde, Vijay
N1 - Funding Information:
Funding This work was supported in part by startup funds from Texas Tech University, College of Human Sciences and Department of Nutritional Sciences and by American Heart Association AIREA grant (20AIREA35170031) to VH. Competing interests NVD has received several US and international patents that protect intellectual property about the use of adenoviruses and its proteins in obesity, diabetes, and related areas. Patient consent for publication Not required. Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article. Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Publisher Copyright:
© Author(s) (or their employer(s)) 2021.
PY - 2021/5/3
Y1 - 2021/5/3
N2 - Introduction Older age is associated with greater prevalence of hyperinsulinemia, type 2 diabetes, and fatty liver disease. These metabolic conditions and aging are bidirectionally linked to mitochondrial dysfunction and telomere attrition. Although effectively addressing these conditions is important for influencing the health and the lifespan, it is particularly challenging in older age. We reported that E4orf1, a protein derived from human adenovirus Ad36, reduces hyperinsulinemia, improves glucose clearance, and protects against hepatic steatosis in younger mice exposed to high fat diet (HFD). Here, we tested if E4orf1 will improve glycemic control, liver fat accumulation, mitochondrial integrity, and reduce telomere attrition in older mice. Research design and methods We used 9-month-old mice that inducibly expressed E4orf1 in adipose tissue and non-E4orf1 expressing control mice. Mice were maintained on a 60% (kcal) HFD for 20 weeks and glycemic control was determined by intraperitoneal glucose tolerance test at week 20. Following 20 weeks of HF-feeding, mice were sacrificed and liver tissues collected to determine the expression of aging genes using qRT-PCR based RT 2 Profiler PCR array. Results Compared with the control mice, E4orf1 significantly improved glycemic control and reduced hepatic steatosis and fibrosis. Additionally, E4orf1 maintained markers of mitochondrial integrity and telomere attrition. Conclusion E4orf1 has the potential to improve glycemic control in older mice, and the improvement persists even after longer term exposure. E4orf1 expression also maintains mitochondrial integrity and telomere attrition, thus delaying age-associated diseases. This provides strong evidence for therapeutic utility of E4orf1 in improving age-associated metabolic and cellular changes that occur with aging in humans.
AB - Introduction Older age is associated with greater prevalence of hyperinsulinemia, type 2 diabetes, and fatty liver disease. These metabolic conditions and aging are bidirectionally linked to mitochondrial dysfunction and telomere attrition. Although effectively addressing these conditions is important for influencing the health and the lifespan, it is particularly challenging in older age. We reported that E4orf1, a protein derived from human adenovirus Ad36, reduces hyperinsulinemia, improves glucose clearance, and protects against hepatic steatosis in younger mice exposed to high fat diet (HFD). Here, we tested if E4orf1 will improve glycemic control, liver fat accumulation, mitochondrial integrity, and reduce telomere attrition in older mice. Research design and methods We used 9-month-old mice that inducibly expressed E4orf1 in adipose tissue and non-E4orf1 expressing control mice. Mice were maintained on a 60% (kcal) HFD for 20 weeks and glycemic control was determined by intraperitoneal glucose tolerance test at week 20. Following 20 weeks of HF-feeding, mice were sacrificed and liver tissues collected to determine the expression of aging genes using qRT-PCR based RT 2 Profiler PCR array. Results Compared with the control mice, E4orf1 significantly improved glycemic control and reduced hepatic steatosis and fibrosis. Additionally, E4orf1 maintained markers of mitochondrial integrity and telomere attrition. Conclusion E4orf1 has the potential to improve glycemic control in older mice, and the improvement persists even after longer term exposure. E4orf1 expression also maintains mitochondrial integrity and telomere attrition, thus delaying age-associated diseases. This provides strong evidence for therapeutic utility of E4orf1 in improving age-associated metabolic and cellular changes that occur with aging in humans.
KW - ageing
KW - hyperglycemia
KW - hyperinsulinism
UR - http://www.scopus.com/inward/record.url?scp=85105319917&partnerID=8YFLogxK
U2 - 10.1136/bmjdrc-2020-002096
DO - 10.1136/bmjdrc-2020-002096
M3 - Article
C2 - 33941552
AN - SCOPUS:85105319917
VL - 9
JO - BMJ Open Diabetes Research and Care
JF - BMJ Open Diabetes Research and Care
SN - 2052-4897
IS - 1
M1 - e002096
ER -