Activation of C/EBP-β by mitohormesis as a therapy for obesity

Project Summary
It is estimated that around 40% of the adult population of the United States is obese and thus at increased risk
for several chronic illnesses. Current weight loss strategies for obese people are often ineffective and come
with serious neurological side effects. This proposal aims to determine whether new strategies to treat and
prevent obesity can be developed from current insights into biological aging.
The transcription factor C/EBP-β regulates the expression of genes involved in fat catabolism and fat stores
mobilization. Preliminary observations suggest that pro-longevity interventions, such as mTORC1 inhibition,
prevent diet-induced obesity in mice and activate C/EBP-β. The nucleoside-analogue reverse-transcriptase
inhibitor (NRTI) adefovir dipivoxil (ADV) also prevents diet-induced obesity and activates C/EBP-β, though
independently of mTORC1 inhibition.
Building on these premises, Aim 1 tests the hypothesis that activation of hepatic C/EBP-β leads to increased
energy expenditure and fat catabolism, with net negative effects on weight and fat stores. Using transgenics
and pharmacological approaches, we will determine the role of hepatic C/EBP-β in lipid metabolism and
homeostasis in the face of obesogenic challenges and morbid obesity. State-of-the-art techniques will be
applied to measure the impact of different isoforms of C/EBP-β on energy balance, glucose homeostasis, and
endocrine regulation of glucose and lipid metabolism.
Aim 2 sets out to determine whether mitohormetic stresses can increase lipid metabolism through activation of
C/EBP-β. Using ADV and other mitochondrial stressors, we will measure activation of mitohormetic pathways
and their connection with increased hepatic oxidation of fatty acids and energy expenditure.
This proposal will be carried out in an institution with strong research programs in both aging and
obesity/diabetes biology. The candidate will receive state of the art training in techniques and analytical tools
necessary to the completion of both aims, including indirect calorimetry, insulin and glucose tolerance testing,
and big data analysis. The candidate will also acquire an in-depth background in energy and nutrient
homeostasis. Altogether, the experiments and training proposed will allow the candidate to build an
independent and successful research program applying insights from geroscience to understand and
investigate nutrient homeostasis, energy balance, and related metabolic disorders.

Grant Number: 5K01DK128128-04
NIH Institute/Center: NIH
Principal Investigator: Alessandro Bitto