This study aimed to investigate the mechanisms by which the association between maternal hyperglycemia and postnatal high-fat diet (HFD) exposure compromises metabolic parameters and hepatic autophagy in adult female pups. For this, Sprague Dawley rats, female pups from nondiabetic (control = FC) or diabetic (FD) mothers, were fed a standard diet (SD) or HFD from weaning until adulthood (n minimum = 5 rats/group): FC/SD, FC/HFD, FD/SD, and FD/HFD. In adulthood, these rats were tested with the oral glucose tolerance test, euthanized, and serum biochemistry parameters were analyzed. Liver samples were collected to evaluate cytokines, redox status, and protein expression autophagy and apoptosis markers. Histomorphometric analyses and an assessment of lipofuscin accumulation were also performed to reflect incomplete autolysosomal digestion. The FC/HFD, FD/SD, and FD/HFD groups showed glucose intolerance and an increased number of hepatocytes. Furthermore, FD/SD and FD/HFD rats showed hyperlipidemia and insulin resistance. Adaptations in hepatic redox pathways were observed in the FD/SD group with increased antioxidant defense marker activity. The FD/SD group also exhibited increased autophagy protein expression, such as p-AMPK, LC3-II/LC3-I, and p62/SQSTM1, lipofuscin accumulation, and caspase-3 activation. After exposure to HFD, the adult female pups of diabetic rats had a reduced p-AMPK and LC3-II/LC3-I ratio, the presence of steatosis, oxidative stress, and inflammation. The reduction of autophagy, stimulated by HFD, may be of vital importance for the susceptibility to metabolic dysfunction-associated fatty liver disease induced by maternal diabetes.

We conducted a meta-analysis to investigate whether diabetes induced by a high-fat diet (HFD) has the potential to alter the process of autophagy in the murine liver.

A systematic literature search was performed with electronic databases (PubMed, EMBASE, Web of Science). Study design, population, intervention, outcome, and risk of bias were analyzed. Given the availability of studies, a quantitative meta-analysis including 23 studies was performed.

The search found 5754 articles, with 48 matching the eligibility criteria, comprising of 1033 animals. The meta-analysis showed that diabetic murines fed with HFD presented an absence of p62 degradation (SMD 4.63, 95 % CI 2.02 to 7.24, p = 0.0005; I² = 77 %), higher expression of p-mTOR/mTOR (SMD 5.20, 95 % CI 1.00 to 9.39, p = 0.01; I² = 78 %), and a decreased p-AMPK/AMPK ratio (SMD -2.02, 95 % CI -3.96 to -0.09, p = 0.04; I² = 85 %) when compared to nondiabetic murines. When associated with streptozotocin, the animals presented decreased ATG-7 and LC3-II. The meta-regression results showed a decrease in autophagy responses due to increased glycemic levels, fat content, and long-term exposure to HFD, and advanced animal age. The common and species-specific protein responses were also consistent with the inhibition of autophagy.

The normal process of autophagy mechanisms in the liver is less competent after HFD consumption. The destabilization of (auto)phagolysosomes contributes to the perpetuation of diabetes, metabolic dysfunction-associated fatty liver disease, and cell death.