Caloric restriction of db/db mice reverts hepatic steatosis and body weight with divergent hepatic metabolism

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver disease and its prevalence is a serious and growing clinical problem. Caloric restriction (CR) is commonly recommended for improvement of obesity-related diseases such as NAFLD. However, the effects of CR on hepatic metabolism remain unknown. We investigated the effects of CR on metabolic dysfunction in the liver of obese diabetic db/db mice. We found that CR of db/db mice reverted insulin resistance, hepatic steatosis, body weight and adiposity to those of db/m mice. 1H-NMR- and UPLC-QTOF-MS-based metabolite profiling data showed significant metabolic alterations related to lipogenesis, ketogenesis, and inflammation in db/db mice. Moreover, western blot analysis showed that lipogenesis pathway enzymes in the liver of db/db mice were reduced by CR. In addition, CR reversed ketogenesis pathway enzymes and the enhanced autophagy, mitochondrial biogenesis, collagen deposition and endoplasmic reticulum stress in db/db mice. In particular, hepatic inflammation-related proteins including lipocalin-2 in db/db mice were attenuated by CR. Hepatic metabolomic studies yielded multiple pathological mechanisms of NAFLD. Also, these findings showed that CR has a therapeutic effect by attenuating the deleterious effects of obesity and diabetes-induced multiple complications.

Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in impaired leptin signaling mice

“…Levels of LCN2 in serum, liver, brain, and adipose tissue are elevated in several murine models of obesity 9,48-50 . In previous studies, we demonstrated that CR attenuates serum, liver, and hippocampus LCN2 levels in db/db and ob/ob mice 48,49 . As circulating LCN2 increases in patients with heart failure, the production of LCN2 in the heart increases 51 , and in vitro treatment of cardiomyocytes with LCN2 causes iron accumulation and oxidative stress through increased 24p3R expression 52,53 .…”

“…This feeding restricted amounts in ob/ob mice maintained the body weight of ob/ob mice and further extended almost 50% of longevity comparable to that of mice fed ad libitum 57 . In Experiment 3, db/m and db/db mice were also randomly divided into four groups at 10 weeks of age; db/m and db/db mice were given free access to food and db/db+CR and db/m+CR mice were transferred to individual cages with restricted food (2 g/day) for 12 weeks, as previously described 49 .…”

Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

“…Thus, acutely activating autophagy with caloric restriction, physical exercise, rapamycin, CRMs (that is, <m>metformin</m> or resveratrol), AMPK-targeting agents or hydrogen sulfide limits non-alcoholic steatohepatitis (NASH) and/or improves various metabolic parameters (including body weight, circulating glucose or triglyceride levels, and insulin sensitivity) in 24-month-old rats 128 , rodents that had been fed a HFD 129–133 , mice acutely or chronically exposed to ethanol 134 as well as in <m> db / db mice</m> or <m> ob / ob mice</m> (which are two genetic models of hyperphagia and thus metabolic syndrome) 130,135,136 . Moreover, activation of autophagy with carbamazepine considerably reduced hepatic fibrosis in a model of α1<m>-antitrypsin deficiency</m>-associated liver disease 137 .…”

The effects of exercise training and caloric restriction on the cardiac oxytocin natriuretic peptide system in the diabetic mouse

“…Moderate CR decreases visceral fat and blood pressure and improves the lipid profile, glucose uptake, and insulin sensitivity, and hearts from CR rodents show an improved ischemic tolerance 13–16. Furthermore, CR preserves pancreatic mass and function by suppressing apoptosis in the db/db mouse,17 attenuates the development of hepatic steatosis in the db/db mice,18 and decreases adiposity in the genetically hyperphagic OLEFT model of type 2 diabetes 19. Taken together, it is clear that the benefits of ET and CR share a common favorable outcome on cardiovascular and metabolic health 20…”