Poster Topical Area: Energy and Macronutrient Metabolism

Location: Hall D

Poster Board Number: 505

P10-106 - Hepatic FGF21 Is Required for Dietary Protein Restriction-Mediated Fatty Acid Oxidation by Activated Brown Adipose Tissue

Monday, Jun 11
8:00 AM – 3:00 PM

Objectives: Cold-activated brown adipose tissue (BAT) has the metabolic flexibility to oxidize glucose and fatty acids via mitochondrial uncoupling protein 1 (UCP1). Dietary protein restriction (PR) also activates BAT and increases energy expenditure, including glucose disposal, but whether this applies to fatty acids is unknown. We tested the hypothesis that PR-induced BAT activation induces fat burning and overall adiposity reduction via the PR-responsive hepatic transcription factor CREBH and its target, the hormone FGF21.


Methods:
Mice were given ad libitum access to a semi-purified complete diet (18% protein, 22% fat, 60% carbohydrates), or protein-free diet in which protein was replaced with isocaloric sucrose, for 7 days at room temperature (22 ºC) or at thermoneutrality (30 ºC). Interscapular BAT was analyzed using RT-qPCR and immunoblotting. BAT substrate utilization was investigated by measuring BAT [3H]palmitate or [14C]2-deoxyglucose uptake. The role of FGF21 was explored using adenoviral short-hairpin RNA, and the roles of CD36 and CREBH analyzed using global knockout mice. Adiposity was measured with EchoMRI.


Results:
PR led to a significant increase in the BAT activation marker UCP1, but not the traditional browning markers PRDM16, PGC1A, or CIDEA, at both room temperature and thermoneutrality, while DIO2 increased significantly at room temperature alone. PR also significantly increased BAT [14C]2-deoxglucose and [3H]palmitate uptake. In mice lacking the fatty acid transporter CD36, PR-mediated activation of UCP1 and DIO2 in BAT were maintained; however, the increase in [3H]palmitate uptake was significantly impaired. FGF21 knockdown significantly reduced PR-mediated BAT UCP1 induction and [3H]palmitate uptake. PR-mediated hepatic FGF21 induction was also dampened in CREBH KO mice, concomitant with reduced UCP1 expression and [3H]palmitate uptake in BAT, and failure to reduce adiposity.


Conclusions:
Activation of BAT by PR conferred metabolic flexibility to oxidize glucose and fatty acids, but differed from cold-induced BAT activation in gene expression and temperature independence. PR-mediated BAT activation, fat uptake, and reduction in adiposity all required FGF21, a liver-derived hormone controlled in part by CREBH.



Funding Source: Research was supported by NIH (R01DK090629, R01AG036712) and Charoen Pokphand Group.
Figure 1: The roles of CD36, FGF21, and CREBH in temperature-independent PR-induced BAT activation

CoAuthors: Humberto TreviƱo-Villarreal – Harvard T.H. Chan School of Public Health; Michael MacArthur – Harvard T.H. Chan School of Public Health; Alexandra Yesian – Harvard T.H. Chan School of Public Health; Sarah Mitchell – Harvard T.H. Chan School of Public Health; James Mitchell – Harvard T.H. Chan School of Public Health

Justin S. Reynolds

Research Assistant
Harvard T.H. Chan School of Public Health
Lexington, Massachusetts