Long-term oral administration of an HNF4α agonist prevents weight gain and hepatic steatosis by promoting increased mitochondrial mass and function

Abstract

We report here that the potent HNF4α agonist N-trans-caffeoyltyramine (NCT) promotes weight loss by inducing an increase in mitochondrial mass and function, including fatty acid oxidation. Previously, we found in a short term trial in obese mice that NCT promoted reversal of hepatic steatosis through a mechanism involving the stimulation of lipophagy by dihydroceramides. NCT led to increased dihydroceramide levels by inhibiting dihydroceramide conversion to ceramides. Here, we were able to administer NCT orally, permitting longer term administration. Mice fed NCT mixed with high fat diet exhibited decreased weight. Examination of RNA-seq data revealed an increase in PPARGC1A, a central regulator of mitochondrial biogenesis. In addition to the decreased hepatic steatosis that we found previously, mice fed a high fat diet containing NCT mice weighed substantially less than control mice fed high fat diet alone. They had increased mitochondrial mass, exhibited increased fatty acid oxidation, and had an increased level of NAD. Markers of liver inflammation such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα), which are important in the progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis were decreased by NCT. There was no evidence of any toxicity from NCT consumption. These results indicate that HNF4α is an important regulator of mitochondrial mass and function and support that use of HNF4α to treat disorders of fatty acid excess, potentially including obesity, NAFLD, and NASH.

Impact of selected novel plant bioactives on improvement of impaired gut barrier function using human primary cell intestinal epithelium

“…Current data on NCT and NFT indicate that its role as an HNF4α agonist can affect many organs and organ systems. The data presented in this contribution show that NCT, and, to a lesser extent, The current body of literature demonstrates NCT and NFT's role in liver health and lipid flux within the liver, as well as gut health (Veeriah et al, 2022). Previous work has demonstrated a role for NCT and NFT in gut barrier function due to its HNF4αagonist properties.…”

“…While the aforementioned data have been generated in pre-clinical studies, it shows proof of concept and provides the basis for further clinical investigation of NCT and gut health. In cell The phenomena noted in cell culture above have been reproduced in obese mice upon administeration of NCT for 10 weeks (Veeriah et al, 2022). What is notable about this study, is that the mice were administered NCT orally, which simulates dietary intake of NCT.…”

Restricting bioenergetic efficiency enhances longevity and mitochondrial redox capacity in Drosophila melanogaster

“…Consequentially, loss of Hnf4 increases carbohydrate dependence and impairs mitochondrial β‐oxidation, rendering fatty acid transport into the mitochondria deficient (Barry & Thummel, 2016 ; Palanker et al., 2009 ). Interestingly, it has been reported that administration of an Hnf4 agonist in conjunction with a HFD led to marked increases in mitochondrial mass, along with increased expression of mitochondrial ETC proteins in mice (Veeriah et al., 2022 ). Additionally, it has been reported that Hnf4 protects against ROS production (Darsigny et al., 2010 ).…”

Perspective: Nutrition’s Next Chapter – Bioactive Gaps and the Microbiome–Mitochondria Axis

“…Food quality scoring systems that aim to capture elements of the food matrix, including degree of processing, relative ratios of nutrients, and missing bioactives, are being developed [ [29] , [30] , [31] ]. Commercial efforts are starting to provide complementary solutions to nutritional guidance such as smart phone applications to personalize and prioritize the whole food selection as well as next-generation products that reincorporate bioactive ingredients into functional foods [ [32] , [33] , [34] , [35] , [36] , [37] ].…”