Abstract
(1) Background: We previously demonstrated that disruption of IP6K1 improves metabolism, protecting mice from high-fat diet-induced obesity, insulin resistance, and non-alcoholic fatty liver disease and steatohepatitis. Age-induced metabolic dysfunction is a major risk factor for metabolic diseases. The involvement of IP6K1 in this process is unknown. (2) Methods: Here, we compared body and fat mass, insulin sensitivity, energy expenditure and serum-, adipose tissue- and liver-metabolic parameters of chow-fed, aged, wild type (aWT) and whole body Ip6k1 knockout (aKO) mice. (3) Results: IP6K1 was upregulated in the adipose tissue and liver of aWT mice compared to young WT mice. Moreover, Ip6k1 deletion blocked age-induced increase in body- and fat-weight and insulin resistance in mice. aKO mice oxidized carbohydrates more efficiently. The knockouts displayed reduced levels of serum insulin, triglycerides, and non-esterified fatty acids. Ip6k1 deletion partly protected age-induced decline of the thermogenic uncoupling protein UCP1 in inguinal white adipose tissue. Targets inhibited by IP6K1 activity such as the insulin sensitivity- and energy expenditure-inducing protein kinases, protein kinase B (PKB/Akt) and AMP-activated protein kinase (AMPK), were activated in the adipose tissue and liver of aKO mice. (4) Conclusions: Ip6k1 deletion maintains healthy metabolism in aging and thus, targeting this kinase may delay the development of age-induced metabolic dysfunction.
Highlights
Targets inhibited by IP6K1 activity such as the insulin sensitivity- and energy expenditure-inducing protein kinases, protein kinase B (PKB/Akt) and AMP-activated protein kinase (AMPK), were activated in the adipose tissue and liver of aKO mice
(4) Conclusions: Ip6k1 deletion maintains healthy metabolism in aging and targeting this kinase may delay the development of age-induced metabolic dysfunction
F4/80 expression was similar in aWT and aKO liver. n = 4 mice per group. (M,N) mRNA expression of p21 was significantly reduced in EWAT and liver of aKO compared to aWT controls. p16 was downregulated in aKO tissues albeit to insignificant levels. n = 4 mice per group. (O,P) Aging upregulated IP6K1 at the protein level in EWAT and liver tissues of WT mice. n = 4 and 5 and 5 and 7 per group for EWAT and liver, respectively
Summary
The increased prevalence of obesity is a major health concern. Aging significantly increases the risks of obesity and obesity-induced co-morbidities such as type-2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), cardiovascular disease and certain types of cancer [1–4]. The mitochondria-enriched adipocytes in the brown adipose tissue (BAT) and brown-like “beige” or “brite” adipocytes in certain WAT depots (for example, the inguinal depot or IWAT) express mitochondrial uncoupling protein 1 (UCP1) to expend energy by thermogenesis. This process facilitates fat loss and improves insulin sensitivity in rodents and humans [8–12]. High-fat diet-fed, whole-body- or adipocyte-specific Ip6k1-KO mice are protected from obesity, hyperinsulinemia, insulin resistance, and hepatic steatosis [33–35]. Aged mice develop metabolic dysfunction despite consuming a normal chow diet (~62%, ~25% and ~13% kcals, from carbohydrate, protein, and fat, respectively). In this study, we used mice of both sexes
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
