We appreciate Wong et al. (1) for their interest in our article (2). The specificity of an antibody could be affected by many factors including the detergents, blocking reagent, and incubating time and temperature as well as the quantity of secondary antibody. Wong et al. claimed that F-box only protein 2 (FBXO2) might not mediate glucose homeostasis in mice. Although the reason for this inconsistency is unclear, the animal models and feeding conditions were different in the two studies. In our study, to specifically explore the metabolic role of FBXO2 in the liver, adenovirus-mediated hepatic overexpression or knockdown was used. In contrast, Wong et al. used FBXO2 global knockout mice. As FBXO2 is widely expressed, the whole-body deletion of FBXO2 might differ from the liver-specific suppression of FBXO2. This phenomenon has been reported in many other studies. For example, severe insulin resistance was only observed in liver-specific insulin receptor (IR) knockout mice and not in skeletal muscle– or fat-specific IR knockout mice (35). In addition, TRB3 was shown to inhibit insulin signaling and promote insulin resistance in the liver (68). However, serum glucose or insulin levels, insulin sensitivity or glucose tolerance, and energy metabolism were not altered in genetic TRB3 deficient mice (9). Therefore, global TRB3 knockout mice displayed normal hepatic insulin signaling and glucose homeostasis (9). Thus, further studies are still needed to extensively investigate the metabolic role of FBXO2 in the liver under different physiological or pathophysiological conditions.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

1.
Wong
S
, et al.
Comment on Liu et al
.
Aberrant expression of FBXO2 disrupts glucose homeostasis through ubiquitin-mediated degradation of insulin receptor in obese mice
.
Diabetes
2017
;
66
:
689
698
(Letter). Diabetes 2020;69:e1. DOI: 10.2337/db19-0975
2.
Liu
B
,
Lu
H
,
Li
D
, et al
.
Aberrant expression of FBXO2 disrupts glucose homeostasis through ubiquitin-mediated degradation of insulin receptor in obese mice
.
Diabetes
2017
;
66
:
689
698
3.
Blüher
M
,
Michael
MD
,
Peroni
OD
, et al
.
Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance
.
Dev Cell
2002
;
3
:
25
38
4.
Michael
MD
,
Kulkarni
RN
,
Postic
C
, et al
.
Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction
.
Mol Cell
2000
;
6
:
87
97
5.
Brüning
JC
,
Michael
MD
,
Winnay
JN
, et al
.
A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance
.
Mol Cell
1998
;
2
:
559
569
6.
Du
K
,
Herzig
S
,
Kulkarni
RN
,
Montminy
M
.
TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver
.
Science
2003
;
300
:
1574
1577
7.
Koo
SH
,
Satoh
H
,
Herzig
S
, et al
.
PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3
.
Nat Med
2004
;
10
:
530
534
8.
Yu
J
,
Xiao
F
,
Guo
Y
, et al
.
Hepatic phosphoserine aminotransferase 1 regulates insulin sensitivity in mice via tribbles homolog 3
.
Diabetes
2015
;
64
:
1591
1602
9.
Okamoto
H
,
Latres
E
,
Liu
R
, et al
.
Genetic deletion of Trb3, the mammalian Drosophila tribbles homolog, displays normal hepatic insulin signaling and glucose homeostasis
.
Diabetes
2007
;
56
:
1350
1356
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.