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Ablation of Copper transporter 1 in adipose tissue impairs
adaptive thermogenesis

Young-seung Lee , Thuy Nguyen Thi Phuong , Tamara korolnek , Byung-Eun Kim Tae-Il Jeon ,
1
1*
1
2
2,
1 Department of Animal Science and Bioindustry, Chonnam National University, Gwangju 61186, Korea
2 Department of Animal and Avian Science, University of Maryland, College Park, MD 20742, USA

Abstract Results

Adipose tissues dissipate an energy as heat through
uncoupling protein-1 (UCP1), a BAT-specific protein. In
response to cold stress, adaptive thermogenesis is induced Ctr1 is upregulated in BAT and iWAT by CTR1 ablation in BAT impairs the
through activation of the electron transport chain (ETC) acute cold exposure and adrenergic lipolysis during cold-induced
including cytochrome c oxidase (CcO), a copper-dependent
enzyme. Recent studies have reported copper is essential stimulation thermogenesis
for maintaining cellular metabolism. However, the exact role
of copper in adaptive thermogenesis of adipose tissue is still
unclear. Here, we show that copper transporter 1 (Ctr1),
which transports Cu across the plasma membrane with high
affinity, is upregulated in BAT and iWAT by cold exposure
with an increase in UCP1. Furthermore, Ctr1 adipose tissue
specific knockout (Ctr1 adq/adq ) mice exhibited that decreased
adaptive thermogenesis and it related with impaired lipolysis.
However, the Cu delivery compound elesclomol (ES)
rescues these events in Ctr1 adq/adq . Taken together, these
findings indicate that Ctr1 plays an essential role in
thermogenic adipocytes via Cu-dependent mechanisms.
Introduction

Adipose tissues, especially brown and beige adipose
tissues, dissipate chemical energy as heat through
thermogenesis. Non-shivering thermogenesis is induced by
cold stress in BAT and WAT, which be converted to BAT- Figure 1. Mice were exposed to room temperature (RT) or
like adipocyte via beigeing in response to cold or β3- 4℃ cold exposure for 12 hours. BAT and iWAT were
adrenergic signaling. β3-adrenergic signaling activates
adenylyl cyclase, which catalyzes the conversion of ATP to collected. Arrowheads indicate the glycosylated full-length
cyclic AMP (cAMP). cAMP activates protein kinase A (PKA) (g) and truncated (t) forms of Ctr1. Ctr1 expression in BAT
and active PKA phosphorylates its target proteins such as was increased by cold exposure along with increased in the
hormone-sensitive lipase (HSL). p-HSL converts thermogenic markers UCP1 and Pgc-1α (top panel). CL Figure 3. Cold exposure caused lipolysis in Ctr1 flox/flox BAT,
triacylglycerols into free fatty acids. Uncoupling protein-1, a induced Ctr1 expression in iWAT (bottom panel). whereas this was prevented in Ctr1 adq/adq BAT. In addition,
master regulator in non-shivering thermogenesis, is CL administration induced pHSL expression in Ctr1 flox/flox ,
activated by β-oxidation of free fatty acids and produces but it suppressed in Ctr1 adq/adq .
heat and four membrane-bound complexes in electron
transport chain (ETC) are responsible for β-oxidation. Ctr1 in adipose tissue is essential for cold
Copper is the enzymatic cofactor required for various adaption in mice
biochemical processes. For example, copper-dependent
enzyme cytochrome c oxidase plays an essential role in The Cu delivery compound elesclomol
ETC to generate ATP or heat. Recent data have shown that (ES) rescues cold-induced hypothermia
copper modulates cAMP-dependent-lipolysis by altering the in Ctr1 adq/adq mice
activity of cAMP degrading phosphodiesterase PDE3B.
However, the exact role of copper in adaptive
thermogenesis of adipose tissue is not fully understood. We
hypothesized that genetic copper transporter 1 ablation in
adipose tissue impairs adaptive thermogenesis during cold
exposure. Our finding indicate that adipose tissue ctr1
deletion impairs cold-induced thermogenesis.
Conclusions
Ctr1 is the major copper influx transporter to mediate
the cellular copper level. Ctr1 is induced in BAT and
iWAT by cold stress and β3-adrenergic signaling.
Furthermore, ctr1 deficiency on adipose tissue inhibits
cold-induced thermogenesis by impairing lipolysis. In Figure 2. The expression of Ctr1 was significantly
decreased by Ctr1 adipose-specific knockout. Ctr1 adq/adq
contrast, the copper delivery compound elesclomol mice exhibited that decreased rectal body temperature 4
restores cold-induced hypothermia in ctr1 adipose hours post cold exposure. Furthermore, core body
tissue knockout mice. Taken together, these findings temperature was statically decreased in Ctr1 adq/adq mice Figure 4. Mice were exposed to 4℃ for the indicated time
suggest that ctr1 plays an essential role in controlling after cold exposure or CL administration at the indicate after vehicle (Veh) or ES injections. ES restored non-
non-shivering thermogenesis in adipose tissues. time. shivering thermogenesis in Ctr1 adq/adq mice.