PhD defence: Liver fat, glucose and lipid metabolism after acute changes in dietary carbohydrate content
Amalie London
PhD thesis
Accumulation of liver triacylglycerol (TG) is associated with impaired glucose metabolism evident already at TG levels >1.5-1.85% (1, 2). The regulation of liver TG content is controlled by several factors with accumulating of liver TG occurring when lipid acquisition is outpacing lipid disposal. Lipid acquisition is driven by fatty acid (FA) availability towards the liver from the diet and release of endogenous FA primarily from the adipose tissue. In the liver, de novo lipogenesis (DNL) is contributing with FA synthesis from non-lipid sources. Subsequently, hepatic FA can be esterified to liver TG. Hepatic lipid disposal is regulated by the capacity to oxidate FA in the liver and to promote ketogenesis along with embedding VLDL particles for secretion as VLDL-TG from the liver.
It is well known that weight loss can reduce liver TG content, but previous studies suggest that liver TG content may be modulated within days in response to changes in dietary macronutrient composition and energy provision (3–7), indicating effects independent of weight loss. Furthermore, in individuals with insulin resistance, a hypocaloric diet with low-carbohydrate content was demonstrated to be superior in reducing liver TG content within 48 hours, when compared to a hypocaloric diet with a high-carbohydrate content (3). However, the effects of acute alterations in dietary carbohydrate and fat availability on liver TG content, glucose and lipid metabolism, particularly under conditions of preserved energy balance, are not yet fully understood. Therefore, this thesis primary objective is to examine the effects of acute (within days) alterations in dietary carbohydrate and fat availability on liver TG content, with an emphasis on elucidating the mechanistic insights underlying the associated changes in glucose and lipid metabolism.
Two human dietary intervention studies were performed.
In study 1, we implemented a randomized cross-over design to evaluate the effect of five days low-carbohydrate, high-fat (LC) diet and five days high-carbohydrate, low-fat (HC) diet during eucaloric conditions in males with overweight or obesity. Liver TG content was measured by 1H-magnetic resonance spectroscopy (1H-MRS). A low dose hyperinsulinemic euglycemic clamp, including the use of stable glucose isotope tracer, was applied to measure changes in hepatic glucose production and hepatic insulin sensitivity. Liver TG content was reduced by 35% after the LC diet concurrently with decreased fasting plasma TG, improvements in the hepatic insulin sensitivity index (HISI) and higher fasting plasma beta-hydroxybutyrate levels. Plasma C16:1n-7, representing the desaturated end product of the DNL, was lower along with a lower respiratory exchange ratio (RER) measured by indirect calorimetry. Thus, indicating that the lipid acquisition was decreased by lower DNL, while the lipid disposal was increased by increased whole body FA oxidation and ketogenesis after the LC diet. In contrast, no changes were observed in liver TG content, fasting plasma TG, hepatic glucose production or hepatic insulin sensitivity after the HC diet. The RER was however increased after HC indicating a lower whole body fat oxidation. During both LC and HC diets peripheral insulin sensitivity was unchanged.
In study 2, we investigated the effects of a two-day matched absolute carbohydrate restriction under two different dietary conditions: very-low-calorie conditions (VLCD) and a low-carbohydrate, high-fat diet (LCHF) that maintained isocaloric conditions. The participants enrolled were males and post-menopausal females who were overweight or obese. This study aimed to decipher the distinct impacts of calorie deficit and carbohydrate restriction, and to separate the effects of low carbohydrate intake from those of low carbohydrate intake combined with increased fat intake. Liver TG content in this study was lower after LCHF but not after VLCD, when compared with after two days of a control diet (CON), respectively. Whole body fat oxidation tended to be higher after LCHF and was higher after VLCD along with higher plasma beta-hydroxybutyrate indicative of increased ketogenesis after both LCHF and VLCD, when compared with after the control diet. Despite lower fasting plasma C-peptide, insulin, glucose and homeostatic model assessment for insulin resistance (HOMA2-IR) after LCHF and VLCD, the postprandial plasma glucose concentrations were higher when reintroducing a carbohydrate-rich mixed meal, when compared with the response after CON. Concurrently, the insulinogenic index (IGI), was lower following LCHF and VLCD indicating an impairment in the initial beta-cell response to the carbohydrate rich mixed meal after two days of carbohydrate restriction as either LCHF or VLCD.
Together the findings from study 1 and study 2 demonstrate that liver TG content can be lowered within days after consuming a low-carbohydrate diet supplemented with fat to maintain eucaloric or isocaloric conditions – the LC diet (study 1) and the LCHF diet (study 2). The lower liver TG content could be ascribed to lower lipid acquisition via lowering of DNL and increased lipid disposal through increased ketogenesis. Both the LC and LCHF diet encompassed favorable fasting parameters for glucose and lipid metabolism. Furthermore, after LC (study 1) it was demonstrated that hepatic insulin sensitivity in the liver was improved together with preserved peripheral insulin sensitivity. However, when reintroducing a liquid mixed meal after two days of LCHF (study 2) the postprandial glucose concentrations were higher when compared with after CON which could be attributed to an impaired initial beta-cell response (lower IGI).
In conclusion, a low-carbohydrate, high-fat diet lowers liver TG content after only two-four days and improves glucose and lipid metabolism in the fasted state. However, acute dietary carbohydrate restriction also leads to higher postprandial plasma glucose concentrations and impaired initial beta-cell response when reintroducing carbohydrates.
2024, 132 pages.
Time
27 November 2024, 14:00
Place
Aud. 1, August Krogh Building, Universitetsparken 13, DK-2100 Copenhagen.
Opponents
Professor Jørgen F.P. Wotjaszewski (chair), Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark.
Professor Amalia Gastaldelli, Institute of Clinical Physiology, CNR, Pisa, Italy.
Adjunct Professor Thure Krarup, Department of Endocrinology, Copenhagen University Hospital Bispebjerg, and Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark.
Main supervisor
Professor Bente Kiens, Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark.
Co-supervisor
Associate Professor Kirstine Nyvold Bojsen-Møller, Department of Endocrinology, Copenhagen University Hospital Hvidovre, and Department of Clinical Medicine, Faculty of Health, University of Copenhagen, Denmark.