Post-weaning exposure to high-sucrose diet induces early non-alcoholic fatty liver disease onset and progression in male mice: role of dysfunctional white adipose tissue

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) particularly among chronic consumers of added sugar-rich diets. However, the impact of early consumption of such diets on NAFLD onset and progression is unclear. Thus, this study sought to characterise metabolic factors involved in NAFLD progression in young mice fed with a high-sucrose diet (HSD). Male Swiss mice were fed HSD or regular chow (CTR) from weaning for up to 60 or 90 days. Obesity development, glucose homeostasis and serum biochemical parameters were determined at each time-point. At day 90, mice were euthanised and white adipose tissue (WAT) collected for lipolytic function assessment and liver for histology, gene expression and cytokines quantification. At day 60, HSD mice presented increased body mass, hypertriglyceridemia, peripheral insulin resistance (IR) and simple steatosis. Upon 90 days on diet, WAT from HSD mice displayed impaired insulin sensitivity, which coincided with increased fasting levels of glucose and free fatty acids (FFA), as well as NAFLD progression to NASH. Transcriptional levels of lipogenic genes, particularly stearoyl-CoA desaturase-1, were consistently increased, leading to hepatic leukocyte infiltration and pro-inflammatory cytokines spillover. Therefore, our dataset supports IR triggering in the WAT as a major factor for dysfunctional release of FFA towards portal circulation and consequent upregulation of lipogenic genes and hepatic inflammatory onset, which decisively concurred for NAFLD-to-NASH progression in young HSD-fed mice. Notwithstanding, this study forewarns against the early introduction of dietary sugars in infant diet, particularly following breastfeeding cessation.

Analysis of the Effect of the TRPC4/TRPC5 Blocker, ML204, in Sucrose-Induced Metabolic Imbalance

“…In addition, studies with healthy- and normal-weight young male volunteers have demonstrated that high-sucrose (HS) diets augment glucose, low-density lipoprotein, and C-reactive protein quantities [ 9 , 10 ]. Similar observations have been made in rodents following HS diet [ 11 , 12 , 13 , 14 ]. This evidence demonstrates that HS causes important metabolic imbalances, which can result in chronic pathologies such as metabolic syndrome (MS), a major health problem which affects the global population at all ages [ 15 , 16 ].…”

Maternal and Offspring Sugar Consumption Increases Perigonadal Adipose Tissue Hypertrophy and Negatively Affects the Testis Histological Organization in Adult Rats

“…The development of alterations in the male reproductive tract has been associated with sugar consumption and metabolic disorders such as for overweight and obesity (Martini et al, 2010;Sadeghi-Bazargani et al, 2013). The progress of these diseases is characterized by an abnormal or excessive accumulation of lipids in the adipocytes of different deposits of WAT (Cinti et al, 2019), as a result of the consumption of high-calorie diets (França et al, 2020;Oliveira et al, 2020). The PAT is one of its largest fat deposits (Berry et al, 2016) and it is the most important for the testis since its extraction in one or both gonads inhibits spermatogenesis (Chu et al, 2010).…”

Integrating the effects of sucrose intake on the brain and white adipose tissue: Could autophagy be a possible link?

“…In C57BL/6 mice, intake of a high‐sucrose diet (3.79 kcal/g, 53% energy from sucrose) for 10 weeks compared with a diet without sucrose (3.1 kcal/g) increased the amount of WAT, adipocyte size in different WAT depots (mesenteric, subcutaneous, epididymal, and perirenal; Figure 1B), and plasma leptin (26). In addition, male Swiss mice fed a diet high in sucrose (3.51 kcal/g, 30% energy from sucrose) for 60 days compared with mice fed an isocaloric diet low in sucrose (3.46 kcal/g, 11% energy from sucrose) showed higher body weight and lower energy intake, increased retroperitoneal and epididymal WAT, and reduced epididymal WAT lipolysis, all evidence supporting that sucrose can alter WAT mass and function without contributing to excess calories (i.e., an adiposity‐independent effect) (8). The increase in WAT mass associated with sucrose intake might be dependent on excess caloric intake or diet duration (48), because C57BL6J mice fed a sucrose‐enriched diet (3.86 kcal/g, 35% energy from sucrose) did not have increased WAT mass or show increased insulin resistance compared with mice fed an isocaloric diet (3.86 kcal/g, 7% energy from sucrose).…”

“…The adiposity-dependent effect proposes that glucose and fructose obtained from sucrose digestion are only a source of excess calories that cause the WAT expansion and hypertrophy that trigger metabolic dysfunction. In contrast, the adiposity-independent effect proposes that glucose and fructose obtained from sucrose digestion can cause metabolic dysfunction and body weight gain without providing excess calories and causing WAT hypertrophy (7)(8)(9)(10). Animal studies using isocaloric diets rich in sucrose show an adiposity-independent effect of dietary sucrose in regulating food intake and body weight.…”