Reversing diet-induced metabolic dysregulation by diet switching leads to altered hepatic de novo lipogenesis and glycerolipid synthesis

Abstract

In humans, low-energy diets rapidly reduce hepatic fat and improve/normalise glycemic control. Due to difficulties in obtaining human liver, little is known about changes to the lipid species and pathway fluxes that occur under these conditions. Using a combination of stable isotope, and targeted metabolomic approaches we investigated the acute (7–9 days) hepatic effects of switching high-fat high-sucrose diet (HFD) fed obese mice back to a chow diet. Upon the switch, energy intake was reduced, resulting in reductions of fat mass and hepatic triacyl- and diacylglycerol. However, these parameters were still elevated compared to chow fed mice, thus representing an intermediate phenotype. Nonetheless, glucose intolerance and hyperinsulinemia were completely normalized. The diet reversal resulted in marked reductions in hepatic de novo lipogenesis when compared to the chow and HFD groups. Compared with HFD, glycerolipid synthesis was reduced in the reversal animals, however it remained elevated above that of chow controls, indicating that despite experiencing a net loss in lipid stores, the liver was still actively esterifying available fatty acids at rates higher than that in chow control mice. This effect likely promotes the re-esterification of excess free fatty acids released from the breakdown of adipose depots during the weight loss period.

Increased hepatic fatty acid polyunsaturation precedes ectopic lipid deposition in the liver in adaptation to high-fat diets in mice

“…We found that glucose tolerance was compromised within 1 week of HFD60 feeding, in good agreement with several studies evaluating short-term effects of HFD feeding [3,8,[28][29][30]. It was previously shown that glucose intolerance induced by an approximately 9-week HFD-feeding protocol can be restored within 1 week by switching to a control diet [31]. Our study now demonstrates that even after longer periods of exposure to an HFD, glucose tolerance is promptly reasserted in response to a reduction in dietary fat intake.…”

The effects of dietary supplementation with inulin and inulin‐propionate ester on hepatic steatosis in adults with non‐alcoholic fatty liver disease

“…17 The current data suggest that in body weight-stable individuals with NAFLD, an increased supply of acetate to the liver from the colonic fermentation of inulin provides surplus acetyl-CoA for DNL and hepatic lipid accretion. Interestingly, diet-induced body weight loss in mice has been shown to markedly reduce insulin levels and rates of hepatic DNL, 19 whilst the expression of hepatic DNL-related genes is also reduced by states of chronic negative energy balance. 20 This may explain the disparate effect of inulin supplementation on liver fat content in the current study compared with our previous investigation when inulin intervention was added to a hypocaloric diet that achieved a~5% reduction in body weight.…”

Proliferation of nutrition sensing preadipocytes upon short term HFD feeding

“…2,[4][5][6][7][8][9] Conversely, removal of HFD was shown to reverse most of these changes. 2,10,11 For some time it was believed, that the total number of fat cells is set during adolescence and a change of fat mass in adults is exclusively caused by hypertrophy. 12,13 However, it was recently demonstrated that hyperplasia plays an important role in obesity and that the ability for an increase in adipocyte number persists for lifetime even after severe weight loss.…”