Research Description

There is a world-wide epidemic of obesity and metabolic syndrome. The consumption of a calorie dense high-fat diet (HFD) was initially thought to be the driver of this epidemic. A recent paradigm shift has placed more attention on dietary sugar as a key culprit in development of obesity. Sugar is highly palatable and generally consumed after a meal when subjects are not hungry. Similarly, sugar sweetened beverages (SSB) are consumed to quench thirst, not hunger, resulting in excess caloric intake. Increased energy intake is the prevailing explanation of how dietary sugar intake leads to poor health outcomes. We provide alternative evidence suggesting that fructose, but not glucose, component of dietary sugar is a master regulator of hepatic energy homeostasis, which is independent of its caloric load. Fructose strongly upregulates de novo lipogenesis, but it also decreases oxidation of dietary fat. The effects of glucose, a sugar monosaccharide of identical caloric load, are different from that of fructose. Thus, nutrients from different dietary sources can stimulate unique metabolic pathways, so that their effects are much more complex than providing dietary calories. The emphasis on reducing total caloric intake may be too simplistic, and it undermines the unique properties of different nutrients.

The long-term goal of our research is to define how the combined intake of sugar and a HFD facilitates the development of non-alcoholic fatty liver disease (NAFLD) and insulin resistance.  We showed that mice fed a HFD supplemented with fructose (HFD+F) in drinking water developed obesity, fatty liver disease and severe insulin resistance, whereas mice on a HFD supplemented with glucose (HFD+G) gained less weight and remained insulin sensitive, as compared to mice fed a HFD alone. Metabolomic and RNA sequence analysis showed that fructose and glucose stimulate unique metabolic pathways, so that fructose supplementation promotes synthesis of free fatty acids, whereas glucose supplementation promotes assembly of inert triglycerides. Hepatic knockdown of ketohexokinase (KHK), the first enzyme of fructose metabolism, improved NAFLD and glucose tolerance in fructose-supplemented mice (Softic, JCI. 2017). In our subsequent studies, we determined that the consumption of fructose, but not glucose-SSB with a HFD decreased mitochondrial FAO. This is mediated via at least three nodes of regulation, including differential effects on malonyl-CoA, mitochondrial morphology, and post-translational modifications (PTMs) of mitochondrial proteins, such as acetylation (Softic et al., Cell Metab. 2019).

The difference between fructose and glucose sweetened beverages was only observed in mice on a HFD, but not in mice on a normal chow diet. Thus there are unique negative interactions between the pathways that govern fructose and fatty acid metabolism.

Future interests of the Softic Lab spans across four major areas of interest. These include:

  1. Effects of fructose on cellular energy homeostasis in the liver.
    1. To promote de novo lipogenesis
    2. To decrease fatty acid oxidation
  2. Uncovering pathways by which fructose induces hepatic insulin resistance.
    1. Identifying unique fructose-induced lipids that can cause insulin resistance
    2. Determining the direct effects of ketohexokinase on hepatic insulin resistance
  3. Delineating regulators of fructose metabolism (ketohexokinase) in the liver and other tissue.
    1. Uncovering the physiologic and genetic regulators of KHK
    2. Identifying alternative pathways of fructose metabolism in the absence of KHK
  4. Clinical studies to assess the effects of dietary sugar on the development of NAFLD in children.
    1. Determine surrogate markers of fructose intake and metabolism
    2. Conduct studies aimed at preventing hepatic fructose metabolism.