Scientific RepoRts | 7: 174 | DOI:10.1038/s41598-017-00267-9
Hyper- and hypo- nutrition studies
of the hepatic transcriptome and
epigenome suggest that PPARα
regulates anaerobic glycolysis
Anthony R. Soltis
, Shmulik Motola
, Santiago Vernia
, Christopher W. Ng
, Norman J.
, Simona Dalin
, Bryan J. Matthews
, Roger J. Davis
& Ernest Fraenkel
Diet plays a crucial role in shaping human health and disease. Diets promoting obesity and insulin
resistance can lead to severe metabolic diseases, while calorie-restricted (CR) diets can improve health
and extend lifespan. In this work, we fed mice either a chow diet (CD), a 16 week high-fat diet (HFD),
or a CR diet to compare and contrast the eects of these diets on mouse liver biology. We collected
transcriptomic and epigenomic datasets from these mice using RNA-Seq and DNase-Seq. We found that
both CR and HFD induce extensive transcriptional changes, in some cases altering the same genes in the
same direction. We used our epigenomic data to infer transcriptional regulatory proteins bound near
these genes that likely inuence their expression levels. In particular, we found evidence for critical roles
played by PPARα and RXRα. We used ChIP-Seq to prole the binding locations for these factors in HFD
and CR livers. We found extensive binding of PPARα near genes involved in glycolysis/gluconeogenesis
and uncovered a role for this factor in regulating anaerobic glycolysis. Overall, we generated extensive
transcriptional and epigenomic datasets from livers of mice fed these diets and uncovered new
functions and gene targets for PPARα.
Diet plays a signicant role in shaping human health and disease. Over nutrition leading to obesity can induce
insulin resistance, a major human health concern that promotes the development of type 2 diabetes and some
. In contrast, caloric restriction can extend lifespan, improve insulin sensitivity, and delay the onset of
age-related diseases, such as diabetes, cardiovascular disease, and neoplasia
. While the broad contrasts between
high-fat diet feeding and calorie restriction are well established, the underlying molecular processes that drive
these physiological and metabolic dierences are incompletely understood.
e liver is a critical regulator of metabolism and is sensitive to dietary changes. e liver maintains normal
glucose homeostasis by suppressing hepatic gluconeogenesis in response to insulin following feeding, while pro-
moting glucose production during fasting
. High-fat diet induced obesity and insulin resistance disrupts these
hepatic mechanisms and promotes hyperglycemia
. Caloric restriction, however, lowers liver fat accumulation
and improves hepatic glucose regulation in obese humans
and reduces the expression of stress and inamma-
tory genes in mouse livers, which may contribute to the anti-aging eects associated with this diet
. e liver,
therefore, is a critical driver of the body’s response to dietary challenges. us, analysis of hepatic responses to
dietary extremes may enhance our understanding of how diet shapes overall human health.
In this study, we proled transcriptional and epigenomic landscapes in the livers of mice fed either a standard
laboratory chow diet (CD), a long-term (16 week) high-fat diet (HFD) to induce obesity and insulin resistance,
or a nutrition-restricted diet to model caloric restriction (CR). Overall, we present a comprehensive analysis of
diet-induced eects on mRNA expression and chromatin accessibility in the mouse liver following HFD and CR.
We found that calorie restriction and high fat feeding have common and independent epigenetic and transcrip-
tomic signatures. We also show that PPARα activation underlies both extreme metabolic situations and identify
new PPARα targets that regulate glucose metabolism.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School,
Worcester, MA, 01605, USA. Anthony R. Soltis, Shmulik Motola and Santiago Vernia contributed equally to this work.
Correspondence and requests for materials should be addressed to E.F. (email: email@example.com)
Received: 12 December 2016
Accepted: 14 February 2017
Published: xx xx xxxx