A high‐fat diet reverses metabolic disorders and premature aging by modulating insulin and IGF1 signaling in SIRT6 knockout mice

Abstract

Mammalian sirtuin 6 (SIRT6) is involved in the regulation of many essential processes, especially metabolic homeostasis. SIRT6 knockout mice undergo premature aging and die at age ~4 weeks. Severe glycometabolic disorders have been found in SIRT6 knockout mice, and whether a dietary intervention can rescue SIRT6 knockout mice remains unknown. In our study, we found that at the same calorie intake, a high‐fat diet dramatically increased the lifespan of SIRT6 knockout mice to 26 weeks (males) and 37 weeks (females), reversed multi‐organ atrophy, and reduced body weight, hypoglycemia, and premature aging. Furthermore, the high‐fat diet partially but significantly normalized the global gene expression profile in SIRT6 knockout mice. Regarding the mechanism, excessive glucose uptake and glycolysis induced by the SIRT6 deficiency were attenuated in skeletal muscle through inhibition of insulin and IGF1 signaling by the high‐fat diet. Similarly, fatty acids but not ketone bodies inhibited glucose uptake, glycolysis, and senescence in SIRT6 knockout fibroblasts, whereas PI3K inhibition antagonized the effects of a high‐fatty‐acid medium in vitro. Overall, the high‐fat diet dramatically reverses numerous consequences of SIRT6 deficiency through modulation of insulin and IGF1 signaling, providing a new basis for elucidation of SIRT6 and fatty‐acid functions and supporting novel therapeutic approaches against metabolic disorders and aging‐related diseases.

Supplementing daidzein in diets improves the reproductive performance, endocrine hormones and antioxidant capacity of multiparous sows

“…IGF-1 can serve as a monitoring signal that allows reproductive events to occur when the nutritional status for successful reproduction has been reached ( Velazquez et al., 2008 ; Bowman et al., 2010 ). In addition, IGF-1 can stimulate the growth of skeletal muscle through the direct or indirect regulation of protein, lipid and carbohydrate metabolism ( Li et al., 2020c ). The increased expression level of IGF- 1 by daidzein may be attributed to the elevated serum oestrogen concentration since the nuclear receptor (oestrogen receptor) activated by oestradiol has been reported to stimulate the local synthesis of IGF-1 ( Klotz et al., 2002 ).…”

SPATA4 improves aging‐induced metabolic dysfunction through promotion of preadipocyte differentiation and adipose tissue expansion

“…The pro‐inflammatory response of adipose tissue manifests a shift from storing to releasing fatty acids (Faty et al, 2012; Zhang et al, 1996). In addition to their role as major sources of cellular fuel, fatty acids can serve as signaling molecules exerting adverse effects on cell function, including interference with insulin signaling (Li et al, 2020). The mRNA levels of inflammatory cytokines as well as activation of NF‐κB was decreased in the WAT of TG old mice compared with WT old mice.…”

“…Tissue and cell samples were prepared in middle RIPA lysis buffer (Biomiga), supplemented with a cocktail of protease (AbMole Bioscience) and phosphatase inhibitors (Solarbio). Western blotting was performed as described previously before (Li et al, 2020). An equal amount of protein was run on 10% SDA‐PAGE and then transferred to a polyvinylidene difluoride (PVDF) membrane (Millipore).…”

A Comprehensive Analysis into the Therapeutic Application of Natural Products as SIRT6 Modulators in Alzheimer’s Disease, Aging, Cancer, Inflammation, and Diabetes

“…Studies have demonstrated that free fatty acid with divergent acyl chain length activates SIRT6 deacetylation by competitively inhibiting the peptide-conjugated myristoyl chain and occupying the hydrophobic pocket of SIRT6 [109]. Klein et al investigated 64 fatty acids along with 190 bioactive lipids for initial targeted screening to identify selective SIRT6 activators, and they found that many of them stimulated SIRT6 with 5-to 12-fold activation [110]. They further identified a SIRT6 activator with more potency and selectivity through a SAR-guided chemical optimization study, where the activation of SIRT6 was mediated through the acceleration of catalytic step transpiring after substrate binding but before NAD+ cleavage [109].…”

“…Free fatty acids comprising 12 to 18 carbons were capable of enhancing SIRT6 deacetylation activity up to 35-fold [109]. One study found that, in SIRT6 knockout mice, intake of a high-fat diet could reverse metabolic disorders and premature aging, because fatty acids might be a better energy source to switch the physiological mechanisms [110]. SIRT6 can control circadian chromatin recruitment of SREBP-1, which regulates genes implicated in fatty acid metabolism.…”