Chemerin affects blood lipid profile of high-fat diet male mice in sedentary and exercise states via glucose and lipid metabolism enzymes

in Endocrine Connections
Authors:
Yi Jia School of Health and Exercise, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China

Search for other papers by Yi Jia in
Current site
Google Scholar
PubMed
Close
https://orcid.org/0000-0002-4827-5340
,
Yanan Yang School of Health and Exercise, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China

Search for other papers by Yanan Yang in
Current site
Google Scholar
PubMed
Close
,
Jing Qu School of Health and Exercise, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China

Search for other papers by Jing Qu in
Current site
Google Scholar
PubMed
Close
,
Lijun Yin School of Health and Exercise, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China

Search for other papers by Lijun Yin in
Current site
Google Scholar
PubMed
Close
, and
Xiaohui Wang School of Health and Exercise, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, China

Search for other papers by Xiaohui Wang in
Current site
Google Scholar
PubMed
Close
https://orcid.org/0000-0001-8355-3871

Correspondence should be addressed to X Wang: wangpan96@126.com or wangxiaohui@sus.edu.cn
Open access

Sign up for journal news

Adipokine chemerin plays important roles in disorders of glucose and lipid metabolism of obesity and obesity-related diseases, and exercise-induced improvement of glucose and lipid metabolism is closely related to the decrease of chemerin, but the mechanisms by which chemerin regulates glucose and lipid metabolism remain unclarified. Hypotestosterone induces male obesity and disorders of glucose and lipid metabolism through androgen receptor (AR) and its target genes: glucose and lipid metabolism-related molecules (including FOXO1, PEPCK, PGC-1α, and SCD1). Recently, the link between them has been reported that chemerin modulated the secretion of androgen. In this study, global chemerin knockout (chemerin (−/−)) mice were established to demonstrate the roles of chemerin in regulating blood glucose and blood lipid of mice under diet (high-fat (HFD) and normal diet) and exercise interventions and then to explore its mechanisms (AR – glucose and lipid metabolism enzymes). We found that the blood lipid and adipocyte size were low accompanied by the improvements in the levels of serum testosterone, gastrocnemius AR, and gastrocnemius FOXO1, SCD1, and PGC-1α in HFD chemerin (−/−) mice, but exercise-induced improvements of these indicators in HFD WT mice were attenuated or abolished in HFD chemerin (−/−) mice. In conclusion, the decrease of chemerin improved the blood lipid profile of HFD male mice at sedentary and exercise states, mediated partly by the increases of testosterone and AR to regulate glucose and lipid metabolism enzymes. To our knowledge, it is the first report that chemerin’s regulation of glucose and lipid metabolism might be mediated by testosterone and AR in vivo.

Abstract

Adipokine chemerin plays important roles in disorders of glucose and lipid metabolism of obesity and obesity-related diseases, and exercise-induced improvement of glucose and lipid metabolism is closely related to the decrease of chemerin, but the mechanisms by which chemerin regulates glucose and lipid metabolism remain unclarified. Hypotestosterone induces male obesity and disorders of glucose and lipid metabolism through androgen receptor (AR) and its target genes: glucose and lipid metabolism-related molecules (including FOXO1, PEPCK, PGC-1α, and SCD1). Recently, the link between them has been reported that chemerin modulated the secretion of androgen. In this study, global chemerin knockout (chemerin (−/−)) mice were established to demonstrate the roles of chemerin in regulating blood glucose and blood lipid of mice under diet (high-fat (HFD) and normal diet) and exercise interventions and then to explore its mechanisms (AR – glucose and lipid metabolism enzymes). We found that the blood lipid and adipocyte size were low accompanied by the improvements in the levels of serum testosterone, gastrocnemius AR, and gastrocnemius FOXO1, SCD1, and PGC-1α in HFD chemerin (−/−) mice, but exercise-induced improvements of these indicators in HFD WT mice were attenuated or abolished in HFD chemerin (−/−) mice. In conclusion, the decrease of chemerin improved the blood lipid profile of HFD male mice at sedentary and exercise states, mediated partly by the increases of testosterone and AR to regulate glucose and lipid metabolism enzymes. To our knowledge, it is the first report that chemerin’s regulation of glucose and lipid metabolism might be mediated by testosterone and AR in vivo.

Introduction

Chemerin, an adipokine discovered in 2007, is mainly produced by adipose tissue and liver, which reaches different tissues and organs of the body through blood circulation (1). In recent years, many studies, including our previous study (2), have shown that chemerin was closely related to obesity and obesity-related disorders of glucose and lipid metabolism. Serum chemerin increased significantly in adults (3) and children (4) with obesity and obesity-related diseases, the more severe syndromes the higher levels of chemerin.

Our previous study found that as short as 4-week aerobic exercise plus dietary control could significantly reduce serum inflammatory factors and improve their glucose and lipid metabolism in obese female adolescents, which was related to the reduction of chemerin (5). In addition, animal experiments also have shown that exercise reduced the level of chemerin in serum and several organs such as liver, gastrocnemius, and adipose tissue (1) and improved glucose and lipid metabolism in obese and diabetic rats and mice (2). For this reason, targeting chemerin/CMKLR1 would be an important strategy to improve the disorders of glucose and lipid metabolism and alleviate the symptoms of obesity and obesity-related diseases. However, the mechanisms of chemerin on blood glucose and lipid in obesity mice at sedentary and exercise states remain unclarified.

The expressions and activities of glucose and lipid metabolism regulators and key enzymes play important roles in maintaining glucose and lipid metabolism homeostasis of body, such as peroxisome proliferator-activated receptor-γ coactlvator-1α (PGC-1α), fork head box O1 (FOXO1), phosphoenolpyruvate carboxykinase (PEPCK), and stearoyl-CoA desaturase-1 (SCD1), and their abnormal expression led to the disruption of glucose and lipid metabolism. Among them, PGC-1α is involved in mitochondrial biogenesis, lipolysis, and fatty acid oxidation (6, 7). It has been reported that skeletal muscle-specific PGC-1α knockout mice have impaired glucose tolerance (8), whereas mice overexpressing PGC-1α have improved glucose and lipid metabolism (9). FOXO1 regulates liver gluconeogenesis mainly by regulating its target gene PEPCK (gluconeogenesis rate-limiting enzyme) (10). Increased expression of FOXO1 and PEPCK causes abnormal glucose and lipid metabolism in mice (11). SCD1 (rate-limiting enzyme that catalyzes the conversion of saturated fatty acids to monounsaturated fatty acids) is closely related to insulin resistance (12). SCD1 inhibitors are considered as a novel potential target for the treatment of diseases such as diabetes and obesity (13).

An increasing body of literature has reported close associations of low androgen levels with obesity, type 2 diabetes, and other chronic diseases possessing disorders of glucolipid metabolism (14, 15). Androgens and androgen receptor (AR) can regulate the expressions of the abovementioned key proteins and enzymes of glucose and lipid metabolism. AR knockout mice have reduced protein levels of skeletal muscle PGC-1α along with increased body weight and body fat percentage, whereas AR agonists increased the protein level of PGC-1α and improved glucose and lipid metabolism of mice (16). FOXO1 is regulated by androgens, and testosterone supplementation reduces the protein level of FOXO1 (17). In addition to through FOXO1 to modulate PEPCK, AR can also directly inhibit the expression and activity of PEPCK, along with increased fasting glucose levels and insulin resistance in liver (18). These results suggest that the regulatory effects of testosterone and AR on glucose and lipid metabolism are related to the regulatory factors and key enzymes of glucose and lipid metabolism, such as PGC-1α, FOXO1, PEPCK, and SCD1.

Interestingly, several studies have found that chemerin/chemerin receptor (CMKLR1) could regulate androgen levels. Serum testosterone was significantly reduced in male CMKLR1 (−/−) mice (19). In in vitro testicular explants, it was observed that recombinant chicken chemerin inhibited testosterone production stimulated by human chorionic gonadotropin (hCG) through CMKLR1, which was related to the decrease of 3β-hydroxysteroid dehydrogenase (3β-HSD) and steroidogenic acute regulatory protein (StAR) (20).

In this study, global chemerin knockout (chemerin (−/−)) mice were generated to demonstrate the roles of chemerin in regulating blood glucose and blood lipid of mice under diet (high-fat (HFD) and normal diet) and exercise interventions and then to explore its mechanisms (AR – glucose and lipid metabolism enzymes pathway). Up to now, no related studies have been reported on the effects of chemerin on AR and its downstream glucose and lipid metabolism enzymes.

Materials and methods

Construction of chemerin (−/−) mice and mice grouping

The chemerin (−/−) mice (C57BL/6 genetic background) were prepared by Shanghai Southern Model Biotechnology Co., Ltd. (Shanghai, China) using Cre-loxP system. In brief, chemerin-floxed (chemerinfl/fl) mice were generated by inserting the flox sequence into both sides of the exon 3 of murine chemerin gene. Mating chemerinfl/fl and DDX4-Cre (C57BL/6 background, obtained from Jackson Laboratory) mice can generate chemerin (−/−) mice. All experiments were conducted with littermate controls.

All experiments were performed in accordance with the approved guidelines by the Ethics Review Committee for Animal Experimentation of Shanghai University of Sport (Approval No.102772021DW009). All the mice were housed in a standard animal facility under conventional conditions: 12 h light:12 h darkness cycle. Following acclimatization to the environment for 7 days, as shown in Fig. 1A, 8-week-old mice were randomly divided into normal diet (ND) and HFD group (n = 8). Then, HFD mice were randomly divided into sedentary group and exercise group (n = 4).

Figure 1
Figure 1

Identification of chemerin knockout in mice. (A) Timeline of diet and exercise interventions. (B) Genotype of wild type (WT) and chemerin (−/−) mice at DNA level. The mRNA levels of chemerin in (C) gastrocnemius and (D) liver of WT and chemerin (−/−) mice. (E) The protein levels of chemerin in multiply organs of WT and chemerin (−/−) mice. eWAT, epididymal white adipose tissue.

Citation: Endocrine Connections 13, 4; 10.1530/EC-23-0484

Screening and identification of chemerin (−/−) mice

The tail tips of 2-week-old pups were cut for 5 mm and the tail DNA was extracted for PCR amplification to screen and identify the genotype of mice. The primers of chemerin (−/−) mice: forward: 5′-TCACTTAGGATGCGGACCTC-3′, reverse: 5′-GTGCCTGCGTTAATGTGCAA-3′; the primers of WT mice: forward: 5′-GGGTCCTCCTAAAGAAACTT-3′, reverse: 5′-TCACCAGTATAATCCAGTCT-3′. The lengths of PCR production are 858 bp and 244 bp, respectively. In addition, the protein and mRNA expression levels of chemerin in liver and gastrocnemius were detected by Western blot and real-time quantitative PCR to verify the knockout and knockout efficiency of chemerin in mice. The primers of chemerin for PCR amplification are forward: 5′-TTGCTGATCTCCCTAGCCCTA-3′ and reverse: 5′-TGGGTGTTTGTGGAACTCCTC-3′.

Diet and exercise intervention

ND and HFD mice were fed with 32 weeks of ND (research diet, D12450J; 10% kcal from fat, 20% kcal from protein, 3.85 kcal/g, SYSE Ltd., Jiangsu, China) and HFD (research diet, D12492; 60% kcal from fat, 20% kcal from protein, 5.24 kcal/g, SYSE Ltd., Jiangsu, China), respectively.

Based on Cordeiro's (21) exercise program with a few modifications. After 3-day treadmill exercise, preconditioned (30 min of training time with 8–10 m/min speed), HFD feeding exercise mice were undertaken 6-week moderate aerobic treadmill running, 60 min/day, 6 days/week, with 10 m/min speed and 0° slope at the first 2 weeks, the speed increased by 1 m/min per week until 14 m/min in the sixth week. At 24 h after the end of the exercise, mice were anesthetized with isoflurane and blood samples were collected from the orbital venous plexus of mice, then mice were sacrificed by cervical dislocation and liver and gastrocnemius were collected.

Detection of blood glucose and blood lipids

The levels of blood glucose and blood lipid in tail vein of mice were measured, including fasting blood glucose (FBG, after 12 h of fasting) detected by blood glucose meter (ACCU-CHEK), and the levels of serum total cholesterol (TC, A111-1-1), triglyceride (TG, A110-1-1), low-density lipoprotein cholesterol (LDL, A113-1-1), and high-density lipoprotein cholesterol (HDL, A112-1-1) were measured using kits from Nanjing Jiancheng Bioengineering Institute. According to the instructions of the kit, the main experimental procedures are as follows: in the transparent 96-well plates, blank wells, calibration wells, and sample wells are set, respectively, and 2.5 μL of distilled water, calibrator, and mouse serum were added to the corresponding wells. A specific volume of detection reagent was added to each well and allowed to react fully at 37°C. Then, a microplate reader was used to measure the absorbance value of each well at a given wavelength. Finally, the lipid levels of each serum sample were calculated using the given formula.

HE staining

A part of liver and adipose tissue fixed by paraformaldehyde were embedded in paraffin and sectioned horizontally with a thickness of 5 μm. The paraffin sections dewaxed with xylene, rehydrated with gradient ethanol, hematoxylin solution staining, followed by 1% hydrochloric acid ethanol, then to eosin solution staining, gradient ethanol solution dehydration, xylene transparency, and neutral resin sealing. The pictures were observed and photographed under 200× of the Olympus microscope.

Detection of serum testosterone level

The level of serum testosterone in mice was detected in duplicate by ELISA (ml001948, Shanghai Enzyme-linked Biotechnology Co., Ltd., Shanghai, China) according to the protocols. The main steps are as follows. All reagents were left at room temperature for 20 min before use, and 50 μL of standards with different concentrations and mouse serum were added into standard wells and sample wells, respectively, then 100 μL of detection antibody labeled with horseradish peroxidase (HRP) were added into each well. Do not add any liquid to the blank well. Incubate the antibody-coated 96-well plate at 37°C for 60 min. Discard the liquid and repeat washing the plate five times, 1 min each time. Spin the washing solution dry and add 50 μL of substrate A and substrate B solutions to each well. Incubate at 37°C without light for 15 min. Add 50 μL of stop solution to each well and measure the optical density value of each well at a wavelength of 450 nm.

Detection of the protein levels of target proteins

The protein levels of chemerin, AR, FOXO1, PEPCK, PGC-1α, and SCD1 in the liver and gastrocnemius muscle of mice were determined by Western blot according to standard procedures. In brief, total protein was extracted from the gastrocnemius and liver with RIPA lysis buffer supplemented with protease inhibitors, PMSF and EDTA. The protein lysates (50 µg) were separated by SDS-PAGE and electrotransferred onto a 0.22 μm nitrocellulose membrane. The membranes were blocked using skimmed milk for 1 h and then incubated in the primary antibodies at 4°C overnight, including chemerin (1:1000, AF2325, R&D), AR (1:3000, 22089-1-AP, Proteintech), FOXO1(1:1000, 2880S, Cell signaling technology), and PGC-1α (1:1000, ab54481, Abcam; 1:5000, 66369-1-Ig, Proteintech), PEPCK (1:1000, 12940S, Cell signaling technology), and SCD1 (1:1000,2438S, Cell Signaling Technology) primary antibodies. The membranes were incubated at room temperature for 1 h with the secondary antibodies (HRP-labeled goat anti-mouse IgG(H+L),1:1000, A0216, Beyotime; goat anti-rabbit IgG(H+L)-HRP antibody, 1:10000, abs20147, absin; mouse anti-goat IgG-HRP,1:2000, sc-2354, Santa Cruz) conjugated to HRP. The immunoreactive bands were visualized with an ECL substrate and exposed using a fully automated chemiluminescence image analysis system (Tanon 5200 Multi, Shanghai Tanon Technology Co., Ltd., Shanghai, China).

Statistical analysis

Statistical Package for the Social Sciences (SPSS) 18.0 (SPSS Inc.) and GraphPad Prism5 (GraphPad Software, San Diego, CA) were used to conduct data analyses. All data are presented as means ± SD. For statistical comparisons between the multiple-group, two-way analysis of variance (ANOVA) was conducted followed by a Bonferroni correction to compare each group. The data were considered significant difference when P-value was <0.05.

Results

Successful establishment of global chemerin knockout mice

The genotypes of the mice were verified at the DNA level. As shown in Fig. 1B, the mice with a band at 244 bp are WT mice, while thos with a band at 858 bp are chemerin (−/−) mice, which were chosen for further identification of chemerin knockout at RNA and protein levels. The mRNA level of chemerin in the gastrocnemius muscle and liver of chemerin (−/−) mice decreased significantly to close undetectable (Fig. 1C and D). In addition, the protein levels of chemerin in multiple organs such as muscle and liver were detected by Western blot and showed the obvious decrease of chemerin in chemerin (−/−) mice (Fig. 1E). These results indicate the successful establishment of chemerin (−/−) mice.

Six weeks of exercise reduced chemerin in the liver and muscle of WT mice but not chemerin (−/−) mice under HFD

We found that under ND, exercise had no effect on the levels of chemerin in the gastrocnemius and liver of both WT and chemerin (−/−) mice (Fig. 2A and C). Under the condition of HFD, exercise could significantly reduce the protein levels of chemerin in the gastrocnemius and liver of WT mice, while had no effect on chemerin (−/−) mice (Fig. 2B and D).

Figure 2
Figure 2

Exercise reduced the levels of chemerin in WT mice but not chemerin (−/−) mice under HFD. The protein levels of chemerin in the gastrocnemius and liver of mice were detected by Western blot under (A and C) normal diet and (B and D) high-fat diet intervention. The blots of chemerin were quantified by ImageJ software and normalized against GAPDH, then the normalized values were compared and statistically analyzed (bar chart). **P < 0.01 vs WT. WT, wild-type mice; WT + EX, WT + exercise; (−/−), chemerin (−/−) mice; (−/−) + EX, chemerin (−/−) + exercise.

Citation: Endocrine Connections 13, 4; 10.1530/EC-23-0484

Chemerin knockout improved blood lipid of WT mice under HFD, while exercise-induced benefits in blood lipid were abolished in chemerin (−/−) mice

As shown in Table 1, there was no significant difference in the levels of blood glucose and blood lipids between chemerin (−/−) and WT mice under ND intervention. Exercise significantly increased serum HDL and decreased serum LDL of WT mice, but no changes were found in exercised chemerin (−/−) mice. Under HFD, serum TG of chemerin (−/−) mice was significantly decreased and serum HDL significantly increased compared with WT group, this indicated that chemerin knockout improved blood lipid of mice under HFD. Exercise decreased the levels of serum TC, TG, and LDL in WT mice fed with HFD but had no significant changes in exercised chemerin (−/−) mice. However, no significant differences in FBG levels between WT and chemerin (−/−) mice have been observed between the exercise and sedentary groups.

Table 1

Effects of chemerin knockout on blood lipid of HFD mice at sedentary and exercise states.

FBG (mmol/L) TC (mmol/L) TG (mmol/L) LDL (mmol/L) HDL (mmol/L)
ND WT 5.70 ± 0.47 5.76 ± 1.03 1.12 ± 0.45 0.85 ± 0.22 1.37 ± 0.04
WT + EX 5.50 ± 0.58 5.45 ± 0.56 0.82 ± 0.07 0.45 ± 0.16* 1.66 ± 0.17**
Chemerin (−/−) 4.80 ± 1.41 5.14 ± 0.53 0.88 ± 0.33 0.66 ± 0.09 1.27 ± 0.08
Chemerin (−/−) + EX 5.00 ± 0.70 5.32 ± 0.87 0.70 ± 0.15 1.00 ± 0.35 1.37 ± 0.38
HFD WT 6.80 ± 0.92 8.74 ± 0.27 1.56 ± 0.10 1.88 ± 0.08 1.19 ± 0.20
WT + EX 6.63 ± 1.16 5.66 ± 1.55** 0.93 ± 0.22** 0.91 ± 0.35** 1.39 ± 0.25
Chemerin (−/−) 6.77 ± 0.60 8.87 ± 1.09 0.87 ± 0.36* 1.94 ± 0.38 1.84 ± 0.49*
Chemerin (−/−) +EX 7.13 ± 0.29 6.91 ± 1.47 0.82 ± 0.13 1.30 ± 0.41 1.37 ± 0.18

Data are presented as mean ± s.d., n = 4 mice/group. *P < 0.05, **P < 0.01 vs WT.

WT, wild-type mice; WT + EX, WT + exercise; chemerin (−/−), chemerin knockout mice; chemerin (−/−) + EX, chemerin (−/−) + exercise.

Chemerin knockout lowered the adipocyte size of WT mice under HFD, while the benefit of exercise-induced adipocyte reduction was attenuated in chemerin (−/−) mice

In order to further explore whether the lack of chemerin affects the lipid metabolism of mice and the role of aerobic exercise in it, we performed HE staining on epididymal white adipose tissue, interscapular brown adipose tissue, and liver of mice in each group. As shown in Fig. 3, under ND intervention, no significant changes in the size of adipocytes in adipose tissue and of adipose vacuoles in liver were observed among the groups. Under HFD intervention, white and brown adipocytes were smaller in chemerin (−/−) mice compared with WT mice, and the adipose vacuoles in liver were also significantly reduced. Aerobic exercise significantly decreased the size of white and brown adipocytes and hepatic steatosis in WT mice, but the beneficial effect of exercise was significantly weakened in chemerin (−/−) mice.

Figure 3
Figure 3

Effects of chemerin knockout on the adipocyte size of HFD mice at sedentary and exercise states. HE staining of (A) epididymal white adipose tissue, (C) interscapular brown adipose tissue, and (E) liver. n = 3 for each group; Scale bars = 50 μm. (B) Statistical result of adipocyte areas in epididymal white adipose tissue; (D) percentage of lipid droplet area in brown adipose tissue; (F) percentage of lipid droplet area in liver. *P < 0.05, **P < 0.01, ***P < 0.001 vs WT; &, P < 0.05 vs chemerin (−/−).

Citation: Endocrine Connections 13, 4; 10.1530/EC-23-0484

Chemerin knockout increased serum testosterone and gastrocnemius AR of mice under HFD, while exercise-induced increases in serum testosterone and gastrocnemius AR were abolished in chemerin (−/−) mice under HFD

Under ND condition (Fig. 4A and C), there was no significant difference in the levels of serum testosterone and muscle AR between the two groups. Under HFD (Fig. 4B and D), the levels of serum testosterone and muscle AR in chemerin (−/−) mice were significantly higher than that in WT mice, which indicated that chemerin downregulated testosterone secretion and muscle AR in male mice; exercise significantly increased serum testosterone and muscle AR of WT mice but had no influences on testosterone and AR in exercised chemerin (−/−) mice.

Figure 4
Figure 4

Effects of chemerin knockout on the levels of serum testosterone and gastrocnemius AR in HFD mice at sedentary and exercise states. (A and B) The serum testosterone in mice under normal diet and high-fat diet were detected by ELISA. (C and D). The protein levels of AR in gastrocnemius of mice under normal diet and high-fat diet were detected by Western blot. The blots of AR were quantified by lmageJ software and normalized against GAPDH, then the normalized values were compared and statistically analyzed (bar chart). * P < 0.05 vs WT.

Citation: Endocrine Connections 13, 4; 10.1530/EC-23-0484

Effects of chemerin knockout on glucose and lipid metabolism enzymes in the gastrocnemius of ND and HFD mice at sedentary and exercise states

As shown in Fig. 5, under ND conditions, the protein levels of PGC-1α, SCD1, and PEPCK between chemerin (−/−) and WT mice were not significantly changed in both sedentary and exercise states. As for FOXO1, chemerin knockout also did not affect the level of FOXO1 in the gastrocnemius of mice, but exercise decreased the protein levels of FOXO1 in WT and chemerin (−/−) mice.

Figure 5
Figure 5

Effects of chemerin knockout on the glucose and lipid metabolism key enzymes of ND mice at sedentary and exercise states. The protein levels of glucose and lipid metabolism enzymes, (A) FOXO1, (B) PEPCK, (C) PGC-1α, and (D) SCD1 in the gastrocnemius of mice under ND were detected by Western blot. The blots were quantified by ImageJ software and normalized against GAPDH, then the normalized values were compared and statistically analyzed (bar chart). n = 4 for each group. ** P < 0.01 vs WT; &&P < 0.01 vs chemerin (−/−). WT, wild-type mice; WT + EX, WT + exercise; (−/−), chemerin knockout mice; (−/−) + EX, (−/−) + exercise.

Citation: Endocrine Connections 13, 4; 10.1530/EC-23-0484

Under HFD, as shown in Fig. 6, the protein levels of FOXO1 and SCD1 decreased while the protein levels of PGC-1α increased in the gastrocnemius of chemerin (−/−) mice compared with WT group. Exercise has similar effects with chemerin knockout on the levels of FOXO1, SCD1, and PGC-1α in the gastrocnemius of HFD WT mice, but exercise-induced decreases of FOXO1 and SCD1 were attenuated and exercise-induced increase of PGC-1α was disappeared in HFD chemerin (−/−) mice. Because exercise reduced FOXO1 and SCD1 in gastrocnemius of HFD WT mice by 45% and 32%, while reduced HFD chemerin (−/−) mice by 34% and 26%, respectively. These results indicated that chemerin knockout affected the levels of FOXO1, SCD1, and PGC-1α in the muscle of HFD mice, and exercise-induced changes of them were weakened (FOXO1 and SCD1) even abolished (PGC-1α) in HFD chemerin (−/−) mice.

Figure 6
Figure 6

Effects of chemerin knockout on the glucose and lipid metabolism key enzymes of HFD mice at sedentary and exercise states. The protein levels of glucose and lipid metabolism enzymes, (A) FOXO1, (B) PEPCK, (C) PGC-1α, and (D) SCD1 in the gastrocnemius of mice under HFD were detected by Western blot. The blots were quantified by ImageJ software and normalized against GAPDH, then the normalized values were compared and statistically analyzed (bar chart). n = 4 for each group. *P < 0.05, **P < 0.01 vs WT; &P < 0.05 vs chemerin (−/−). WT, wild-type mice; WT + EX, WT + exercise; (−/−), chemerin knockout mice; (−/−) + EX, (−/−) + exercise.

Citation: Endocrine Connections 13, 4; 10.1530/EC-23-0484

Discussion

Decreased chemerin contributes to the improvement of blood lipid of HFD mice at sedentary and exercise states

Results from both clinical studies and animal experiments suggest that exercise-induced reductions of chemerin are closely associated with exercise-induced improvements of glucolipid metabolism in obesity and obesity-related diseases (2, 5, 22). In this study, we found that global knockdown of chemerin improved blood lipid of HFD male mice at sedentary state; furthermore, exercise-induced improvements of blood lipid were abolished in HFD chemerin (−/−) mice. Consistent with this, the absence of chemerin attenuated the adverse effects of HFD on adipocyte enlargement in WAT, BAT, and liver but also weakened the beneficial effects of exercise on them. These results indicated that chemerin deficiency contributed to the improvements of blood lipid and reduction of adipocyte sizes of HFD mice, and exercise-induced improvements of the abovementioned indicators were likely to be mediated by the decreased chemerin because the benefits of exercise were disappeared in chemerin (−/−) mice (chemerin is too low to decrease by exercise).

However, although many studies have shown a positive correlation between chemerin level and poor glycemic control (23), our results did not find the effect of chemerin knockout on blood glucose levels of HFD mice at sedentary and exercise states. As for the reason, we speculate that chemerin deficiency maybe has more sensitive and power in improving blood lipid than influencing blood glucose, which needs further investigation. In addition, the levels of FBG were not changed by chemerin knockout and exercise under HFD and ND states, which may be related to maintaining a normal range of FBG after HFD, knockout and exercise intervention, and more sensitive indicators about glucose homeostasis are needed for studies in future.

Chemerin-regulated blood lipid of HFD mice was fulfilled by modulating glucose and lipid metabolism key enzymes associated with testosterone and AR

As mentioned in the Introduction, several regulatory factors and key enzymes related to glucose and lipid metabolism (FOXO1, PGC-1α, SCD1, and PEPCK) were AR’s downstream molecules, so we examined the levels of these proteins in the gastrocnemius of ND and HFD chemerin (−/−) mice at sedentary and exercise states, and found that: (i) at the sedentary state, FOXO1 and SCD1 decreased and PGC-1α increased in the gastrocnemius of HFD chemerin (−/−) mice, accompanied by the improvement of TG and HDL; (ii) at the exercise state, exercise-induced increase of PGC-1α was abolished and exercise-induced decreases of FOXO1 and SCD1 were attenuated in HFD chemerin (−/−) mice, accompanied by the disappearance of exercise-induced reductions of TG, TC, and LDL. These results suggested that the improved effect of chemerin deficiency or chemerin decrease on the blood lipid profile of HFD male mice at sedentary and exercise states was through AR’s downstream glucose and lipid metabolism enzymes.

In 2014, Li (24) et al. first reported the direct biological effects of chemerin/CMKLR1 on mammalian male gonads, pointing out that chemerin can be used as a novel gonadal hormone production regulator. In primary cultured Leydig cells, treatment with chemerin at dose of 1, 10, or 100 nM significantly reduced hCG-induced testosterone secretion and inhibited the levels of 3β-HSD. In addition, recombinant chemerin also reduced the sperm quality of rooster, affecting fertility (20). These results indicate that chemerin/CMKLR1 play important roles in regulating testosterone secretion and male reproduction. It has been reported that mice aged 10–15 months were defined as middle-aged, although these mice begin to show aging changes. Mice that are at least 18 months old can be defined as aged, at which time biomarkers of aging can be significantly detected (25). This article found that exercise-induced improvements of blood lipid and adipocyte sizes in HFD male mice at middle age (lower testosterone levels compared with young mice) was through the decreased chemerin to upregulating testosterone level, and another work of our group has found the similar results in young male mice (unpublished data), which broaden the modulation of chemerin on testosterone to multiple age groups.

Considering the regulation of chemerin on testosterone/AR as well as the importance of reduced chemerin (2, 5, 26) and increased testosterone/AR (15, 27) on the prevention and treatment of glucose and lipid metabolism disorders in obesity and obesity-related diseases, we hypothesized that exercise-induced reductions of chemerin in serum and peripheral tissues in HFD male mice were associated with the increases of testosterone and AR signaling. For giving a clear answer, we examined serum testosterone levels and AR protein levels in the liver and gastrocnemius muscle of HFD and ND chemerin (−/−) mice at sedentary and exercise states. We found that chemerin knockout increased significantly serum testosterone and muscular AR only in HFD male mice at sedentary state, and exercise-induced increases of serum testosterone and muscle AR and improvement of blood lipid in HFD WT mice were abolished in HFD chemerin (−/−) mice, which indicated that the effect of chemerin on blood lipid of HFD mice at sedentary and exercise states were likely to be associated with testosterone and AR. This study provided the evidence that chemerin may be a potential bridge linking gonadal steroid synthesis, obesity, and metabolic diseases.

Conclusion

Chemerin deficiency, either global chemerin knockout or exercise-induced chemerin reduction, lowered the blood lipid of HFD male mice at sedentary or exercise states, which might be mediated partly by the increases of testosterone and AR, then regulating AR’s downstream moleculesrelated to glucose and lipid metabolism such as PGC-1α, FOXO1, and SCD1 (as shown in Fig. 7). The current study is beneficial for further understanding the mechanisms of chemerin on glucose and lipid metabolism and for supporting new insight ‘chemerin might be a bridge linking synthesizing sex hormones, obesity, and metabolic diseases’.

Figure 7
Figure 7

Diagram of full text summary.

Citation: Endocrine Connections 13, 4; 10.1530/EC-23-0484

Strengths and limitation

This study has some strengths, for example, using chemerin (−/−) mice to investigate the influence of chemerin on glucose and lipid metabolism at diet intervention (HFD vs ND) and exercise intervention, and first reported the link of chemerin, testosterone/AR, glucose, and lipid metabolism enzymes in vivo. However, this study also has a limitation, not demonstrating directly that the modulation of chemerin on glucose and lipid metabolism enzymes was mediated by testosterone and AR, which could be demonstrated by establishing castration and AR antagonist models (AR inhibitor or AR knockout) of chemerin knockout male mice in future.

Declaration of interest

The authors declare that they have no conflict of interest.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 31872801) and Shanghai Key Lab of Human Performance (Shanghai University of Sport) (No. 11DZ2261100).

Data availability statement

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author contribution statement

All authors contributed to the development of the animal experiments and the analysis and drafting of the manuscript. JY was a major contributor in writing the manuscript. YY contributed mainly to data collection and data analysis. QJ and YL contributed to experimental research. WX contributed to the design of the study. All authors read and approved the final manuscript.

References

  • 1

    Helfer G, & Wu QF. Chemerin: a multifaceted adipokine involved in metabolic disorders. Journal of Endocrinology 2018 238 R79R94. (https://doi.org/10.1530/JOE-18-0174)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Lin X, Yang Y, Qu J, & Wang X. Aerobic exercise decreases chemerin/CMKLR1 in the serum and peripheral metabolic organs of obesity and diabetes rats by increasing PPARγ. Nutrition and Metabolism 2019 16 17. (https://doi.org/10.1186/s12986-019-0344-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Karczewska-Kupczewska M, Nikołajuk A, Stefanowicz M, Matulewicz N, Kowalska I, & Strączkowski M. Serum and adipose tissue chemerin is differentially related to insulin sensitivity. Endocrine Connections 2020 9 360369. (https://doi.org/10.1530/EC-20-0084)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Landgraf K, Friebe D, Ullrich T, Kratzsch J, Dittrich K, Herberth G, Adams V, Kiess W, Erbs S, & Körner A. Chemerin as a mediator between obesity and vascular inflammation in children. Journal of Clinical Endocrinology and Metabolism 2012 97 E556E564. (https://doi.org/10.1210/jc.2011-2937)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Liu M, Lin X, & Wang X. Decrease in serum chemerin through aerobic exercise plus dieting and its association with mitigation of cardio-metabolic risk in obese female adolescents. Journal of Pediatric Endocrinology and Metabolism 2018 31 127135. (https://doi.org/10.1515/jpem-2017-0431)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Wu H, Deng X, Shi Y, Su Y, Wei J, & Duan H. PGC-1α, glucose metabolism and type 2 diabetes mellitus. Journal of Endocrinology 2016 229 R99R115. (https://doi.org/10.1530/JOE-16-0021)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Cheng CF, Ku HC, & Lin H. PGC-1α as a pivotal factor in lipid and metabolic regulation. International Journal of Molecular Sciences 2018 19. (https://doi.org/10.3390/ijms19113447)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Hatazawa Y, Minami K, Yoshimura R, Onishi T, Manio MC, Inoue K, Sawada N, Suzuki O, Miura S, & Kamei Y. Deletion of the transcriptional coactivator PGC1α in skeletal muscles is associated with reduced expression of genes related to oxidative muscle function. Biochemical and Biophysical Research Communications 2016 481 251258. (https://doi.org/10.1016/j.bbrc.2016.10.133)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Zhang L, Zhou Y, Wu W, Hou L, Chen H, Zuo B, Xiong Y, & Yang J. Skeletal muscle-specific overexpression of PGC-1α induces fiber-type conversion through enhanced mitochondrial respiration and fatty acid oxidation in mice and pigs. International Journal of Biological Sciences 2017 13 11521162. (https://doi.org/10.7150/ijbs.20132)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Langlet F, Haeusler RA, Lindén D, Ericson E, Norris T, Johansson A, Cook JR, Aizawa K, Wang L, Buettner C, et al.Selective inhibition of FOXO1 activator/repressor balance modulates hepatic glucose handling. Cell 2017 171 824835.e18. (https://doi.org/10.1016/j.cell.2017.09.045)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Li Y, Ma Z, Jiang S, Hu W, Li T, Di S, Wang D, & Yang Y. A global perspective on FOXO1 in lipid metabolism and lipid-related diseases. Progress in Lipid Research 2017 66 4249. (https://doi.org/10.1016/j.plipres.2017.04.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Dziewulska A, Dobosz AM, Dobrzyn A, Smolinska A, Kolczynska K, Ntambi JM, & Dobrzyn P. SCD1 regulates the AMPK/SIRT1 pathway and histone acetylation through changes in adenine nucleotide metabolism in skeletal muscle. Journal of Cellular Physiology 2020 235 11291140. (https://doi.org/10.1002/jcp.29026)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Iida T, Ubukata M, Mitani I, Nakagawa Y, Maeda K, Imai H, Ogoshi Y, Hotta T, Sakata S, Sano R, et al.Discovery of potent liver-selective stearoyl-CoA desaturase-1 (SCD1) inhibitors, thiazole-4-acetic acid derivatives, for the treatment of diabetes, hepatic steatosis, and obesity. European Journal of Medicinal Chemistry 2018 158 832852. (https://doi.org/10.1016/j.ejmech.2018.09.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Corona G, Giagulli VA, Maseroli E, Vignozzi L, Aversa A, Zitzmann M, Saad F, Mannucci E, & Maggi M. Therapy of endocrine disease: testosterone supplementation and body composition: results from a meta-analysis study. European Journal of Endocrinology 2016 174 R99R116. (https://doi.org/10.1530/EJE-15-0262)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Dubois V, Laurent MR, Jardi F, Antonio L, Lemaire K, Goyvaerts L, Deldicque L, Carmeliet G, Decallonne B, Vanderschueren D, et al.Androgen deficiency exacerbates high-fat diet-induced metabolic alterations in male mice. Endocrinology 2016 157 648665. (https://doi.org/10.1210/en.2015-1713)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Usui T, Kajita K, Kajita T, Mori I, Hanamoto T, Ikeda T, Okada H, Taguchi K, Kitada Y, Morita H, et al.Elevated mitochondrial biogenesis in skeletal muscle is associated with testosterone-induced body weight loss in male mice. FEBS Letters 2014 588 19351941. (https://doi.org/10.1016/j.febslet.2014.03.051)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Pal M, & Gupta S. Testosterone supplementation improves glucose homeostasis despite increasing hepatic insulin resistance in male mouse model of type 2 diabetes mellitus. Nutrition and Diabetes 2016 6 e236. (https://doi.org/10.1038/nutd.2016.45)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Lin HY, Yu IC, Wang RS, Chen YT, Liu NC, Altuwaijri S, Hsu CL, Ma WL, Jokinen J, Sparks JD, et al.Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor. Hepatology 2008 47 19241935. (https://doi.org/10.1002/hep.22252)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Zhao H, Yan D, Xiang L, Huang C, Li J, Yu X, Huang B, Wang B, Chen J, Xiao T, et al.Chemokine-like receptor 1 deficiency leads to lower bone mass in male mice. Cellular and Molecular Life Sciences 2019 76 355367. (https://doi.org/10.1007/s00018-018-2944-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Estienne A, Reverchon M, Partyka A, Bourdon G, Grandhaye J, Barbe A, Caldas-Silveira E, Rame C, Niżański W, Froment P, et al.Chemerin impairs in vitro testosterone production, sperm motility, and fertility in chicken: possible involvement of its receptor CMKLR1. Cells 2020 9 1599. (https://doi.org/10.3390/cells9071599)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Cordeiro AV, Brícola RS, Braga RR, Lenhare L, Silva VRR, Anaruma CP, Katashima CK, Crisol BM, Simabuco FM, Silva ASR, et al.Aerobic exercise training induces the mitonuclear imbalance and UPRmt in the skeletal muscle of aged mice. Journals of Gerontology 2020 75 22582261. (https://doi.org/10.1093/gerona/glaa059)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Neuparth MJ, Proença JB, Santos-Silva A, & Coimbra S. The positive effect of moderate walking exercise on chemerin levels in Portuguese patients with type 2 diabetes mellitus. Journal of Investigative Medicine 2014 62 350353. (https://doi.org/10.2310/JIM.0000000000000025)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Léniz A, González M, Besné I, Carr-Ugarte H, Gómez-García I, & Portillo MP. Role of chemerin in the control of glucose homeostasis. Molecular and Cellular Endocrinology 2022 541 111504. (https://doi.org/10.1016/j.mce.2021.111504)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Li L, Ma P, Huang C, Liu Y, Zhang Y, Gao C, Xiao T, Ren PG, Zabel BA, & Zhang JV. Expression of chemerin and its receptors in rat testes and its action on testosterone secretion. Journal of Endocrinology 2014 220 155163. (https://doi.org/10.1530/JOE-13-0275)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Dutta S, & Sengupta P. Men and mice: relating their ages. Life Sciences 2016 152 244248. (https://doi.org/10.1016/j.lfs.2015.10.025)

  • 26

    Ahmadabadi F, Nakhaei H, Mogharnasi M, & Huang CJ. Aerobic interval training improves irisin and chemerin levels of both liver and visceral adipose tissues and circulating asprosin in rats with metabolic syndrome. Physiology International 2021 108 383397. (https://doi.org/10.1556/2060.2021.00182)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Navarro G, Allard C, Xu W, & Mauvais-Jarvis F. The role of androgens in metabolism, obesity, and diabetes in males and females. Obesity 2015 23 713719. (https://doi.org/10.1002/oby.21033)

    • PubMed
    • Search Google Scholar
    • Export Citation

 

  • Collapse
  • Expand
  • Figure 1

    Identification of chemerin knockout in mice. (A) Timeline of diet and exercise interventions. (B) Genotype of wild type (WT) and chemerin (−/−) mice at DNA level. The mRNA levels of chemerin in (C) gastrocnemius and (D) liver of WT and chemerin (−/−) mice. (E) The protein levels of chemerin in multiply organs of WT and chemerin (−/−) mice. eWAT, epididymal white adipose tissue.

  • Figure 2

    Exercise reduced the levels of chemerin in WT mice but not chemerin (−/−) mice under HFD. The protein levels of chemerin in the gastrocnemius and liver of mice were detected by Western blot under (A and C) normal diet and (B and D) high-fat diet intervention. The blots of chemerin were quantified by ImageJ software and normalized against GAPDH, then the normalized values were compared and statistically analyzed (bar chart). **P < 0.01 vs WT. WT, wild-type mice; WT + EX, WT + exercise; (−/−), chemerin (−/−) mice; (−/−) + EX, chemerin (−/−) + exercise.

  • Figure 3

    Effects of chemerin knockout on the adipocyte size of HFD mice at sedentary and exercise states. HE staining of (A) epididymal white adipose tissue, (C) interscapular brown adipose tissue, and (E) liver. n = 3 for each group; Scale bars = 50 μm. (B) Statistical result of adipocyte areas in epididymal white adipose tissue; (D) percentage of lipid droplet area in brown adipose tissue; (F) percentage of lipid droplet area in liver. *P < 0.05, **P < 0.01, ***P < 0.001 vs WT; &, P < 0.05 vs chemerin (−/−).

  • Figure 4

    Effects of chemerin knockout on the levels of serum testosterone and gastrocnemius AR in HFD mice at sedentary and exercise states. (A and B) The serum testosterone in mice under normal diet and high-fat diet were detected by ELISA. (C and D). The protein levels of AR in gastrocnemius of mice under normal diet and high-fat diet were detected by Western blot. The blots of AR were quantified by lmageJ software and normalized against GAPDH, then the normalized values were compared and statistically analyzed (bar chart). * P < 0.05 vs WT.

  • Figure 5

    Effects of chemerin knockout on the glucose and lipid metabolism key enzymes of ND mice at sedentary and exercise states. The protein levels of glucose and lipid metabolism enzymes, (A) FOXO1, (B) PEPCK, (C) PGC-1α, and (D) SCD1 in the gastrocnemius of mice under ND were detected by Western blot. The blots were quantified by ImageJ software and normalized against GAPDH, then the normalized values were compared and statistically analyzed (bar chart). n = 4 for each group. ** P < 0.01 vs WT; &&P < 0.01 vs chemerin (−/−). WT, wild-type mice; WT + EX, WT + exercise; (−/−), chemerin knockout mice; (−/−) + EX, (−/−) + exercise.

  • Figure 6

    Effects of chemerin knockout on the glucose and lipid metabolism key enzymes of HFD mice at sedentary and exercise states. The protein levels of glucose and lipid metabolism enzymes, (A) FOXO1, (B) PEPCK, (C) PGC-1α, and (D) SCD1 in the gastrocnemius of mice under HFD were detected by Western blot. The blots were quantified by ImageJ software and normalized against GAPDH, then the normalized values were compared and statistically analyzed (bar chart). n = 4 for each group. *P < 0.05, **P < 0.01 vs WT; &P < 0.05 vs chemerin (−/−). WT, wild-type mice; WT + EX, WT + exercise; (−/−), chemerin knockout mice; (−/−) + EX, (−/−) + exercise.

  • Figure 7

    Diagram of full text summary.

  • 1

    Helfer G, & Wu QF. Chemerin: a multifaceted adipokine involved in metabolic disorders. Journal of Endocrinology 2018 238 R79R94. (https://doi.org/10.1530/JOE-18-0174)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Lin X, Yang Y, Qu J, & Wang X. Aerobic exercise decreases chemerin/CMKLR1 in the serum and peripheral metabolic organs of obesity and diabetes rats by increasing PPARγ. Nutrition and Metabolism 2019 16 17. (https://doi.org/10.1186/s12986-019-0344-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Karczewska-Kupczewska M, Nikołajuk A, Stefanowicz M, Matulewicz N, Kowalska I, & Strączkowski M. Serum and adipose tissue chemerin is differentially related to insulin sensitivity. Endocrine Connections 2020 9 360369. (https://doi.org/10.1530/EC-20-0084)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Landgraf K, Friebe D, Ullrich T, Kratzsch J, Dittrich K, Herberth G, Adams V, Kiess W, Erbs S, & Körner A. Chemerin as a mediator between obesity and vascular inflammation in children. Journal of Clinical Endocrinology and Metabolism 2012 97 E556E564. (https://doi.org/10.1210/jc.2011-2937)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Liu M, Lin X, & Wang X. Decrease in serum chemerin through aerobic exercise plus dieting and its association with mitigation of cardio-metabolic risk in obese female adolescents. Journal of Pediatric Endocrinology and Metabolism 2018 31 127135. (https://doi.org/10.1515/jpem-2017-0431)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Wu H, Deng X, Shi Y, Su Y, Wei J, & Duan H. PGC-1α, glucose metabolism and type 2 diabetes mellitus. Journal of Endocrinology 2016 229 R99R115. (https://doi.org/10.1530/JOE-16-0021)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Cheng CF, Ku HC, & Lin H. PGC-1α as a pivotal factor in lipid and metabolic regulation. International Journal of Molecular Sciences 2018 19. (https://doi.org/10.3390/ijms19113447)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Hatazawa Y, Minami K, Yoshimura R, Onishi T, Manio MC, Inoue K, Sawada N, Suzuki O, Miura S, & Kamei Y. Deletion of the transcriptional coactivator PGC1α in skeletal muscles is associated with reduced expression of genes related to oxidative muscle function. Biochemical and Biophysical Research Communications 2016 481 251258. (https://doi.org/10.1016/j.bbrc.2016.10.133)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Zhang L, Zhou Y, Wu W, Hou L, Chen H, Zuo B, Xiong Y, & Yang J. Skeletal muscle-specific overexpression of PGC-1α induces fiber-type conversion through enhanced mitochondrial respiration and fatty acid oxidation in mice and pigs. International Journal of Biological Sciences 2017 13 11521162. (https://doi.org/10.7150/ijbs.20132)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Langlet F, Haeusler RA, Lindén D, Ericson E, Norris T, Johansson A, Cook JR, Aizawa K, Wang L, Buettner C, et al.Selective inhibition of FOXO1 activator/repressor balance modulates hepatic glucose handling. Cell 2017 171 824835.e18. (https://doi.org/10.1016/j.cell.2017.09.045)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Li Y, Ma Z, Jiang S, Hu W, Li T, Di S, Wang D, & Yang Y. A global perspective on FOXO1 in lipid metabolism and lipid-related diseases. Progress in Lipid Research 2017 66 4249. (https://doi.org/10.1016/j.plipres.2017.04.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Dziewulska A, Dobosz AM, Dobrzyn A, Smolinska A, Kolczynska K, Ntambi JM, & Dobrzyn P. SCD1 regulates the AMPK/SIRT1 pathway and histone acetylation through changes in adenine nucleotide metabolism in skeletal muscle. Journal of Cellular Physiology 2020 235 11291140. (https://doi.org/10.1002/jcp.29026)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Iida T, Ubukata M, Mitani I, Nakagawa Y, Maeda K, Imai H, Ogoshi Y, Hotta T, Sakata S, Sano R, et al.Discovery of potent liver-selective stearoyl-CoA desaturase-1 (SCD1) inhibitors, thiazole-4-acetic acid derivatives, for the treatment of diabetes, hepatic steatosis, and obesity. European Journal of Medicinal Chemistry 2018 158 832852. (https://doi.org/10.1016/j.ejmech.2018.09.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Corona G, Giagulli VA, Maseroli E, Vignozzi L, Aversa A, Zitzmann M, Saad F, Mannucci E, & Maggi M. Therapy of endocrine disease: testosterone supplementation and body composition: results from a meta-analysis study. European Journal of Endocrinology 2016 174 R99R116. (https://doi.org/10.1530/EJE-15-0262)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Dubois V, Laurent MR, Jardi F, Antonio L, Lemaire K, Goyvaerts L, Deldicque L, Carmeliet G, Decallonne B, Vanderschueren D, et al.Androgen deficiency exacerbates high-fat diet-induced metabolic alterations in male mice. Endocrinology 2016 157 648665. (https://doi.org/10.1210/en.2015-1713)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Usui T, Kajita K, Kajita T, Mori I, Hanamoto T, Ikeda T, Okada H, Taguchi K, Kitada Y, Morita H, et al.Elevated mitochondrial biogenesis in skeletal muscle is associated with testosterone-induced body weight loss in male mice. FEBS Letters 2014 588 19351941. (https://doi.org/10.1016/j.febslet.2014.03.051)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Pal M, & Gupta S. Testosterone supplementation improves glucose homeostasis despite increasing hepatic insulin resistance in male mouse model of type 2 diabetes mellitus. Nutrition and Diabetes 2016 6 e236. (https://doi.org/10.1038/nutd.2016.45)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Lin HY, Yu IC, Wang RS, Chen YT, Liu NC, Altuwaijri S, Hsu CL, Ma WL, Jokinen J, Sparks JD, et al.Increased hepatic steatosis and insulin resistance in mice lacking hepatic androgen receptor. Hepatology 2008 47 19241935. (https://doi.org/10.1002/hep.22252)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Zhao H, Yan D, Xiang L, Huang C, Li J, Yu X, Huang B, Wang B, Chen J, Xiao T, et al.Chemokine-like receptor 1 deficiency leads to lower bone mass in male mice. Cellular and Molecular Life Sciences 2019 76 355367. (https://doi.org/10.1007/s00018-018-2944-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Estienne A, Reverchon M, Partyka A, Bourdon G, Grandhaye J, Barbe A, Caldas-Silveira E, Rame C, Niżański W, Froment P, et al.Chemerin impairs in vitro testosterone production, sperm motility, and fertility in chicken: possible involvement of its receptor CMKLR1. Cells 2020 9 1599. (https://doi.org/10.3390/cells9071599)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Cordeiro AV, Brícola RS, Braga RR, Lenhare L, Silva VRR, Anaruma CP, Katashima CK, Crisol BM, Simabuco FM, Silva ASR, et al.Aerobic exercise training induces the mitonuclear imbalance and UPRmt in the skeletal muscle of aged mice. Journals of Gerontology 2020 75 22582261. (https://doi.org/10.1093/gerona/glaa059)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Neuparth MJ, Proença JB, Santos-Silva A, & Coimbra S. The positive effect of moderate walking exercise on chemerin levels in Portuguese patients with type 2 diabetes mellitus. Journal of Investigative Medicine 2014 62 350353. (https://doi.org/10.2310/JIM.0000000000000025)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Léniz A, González M, Besné I, Carr-Ugarte H, Gómez-García I, & Portillo MP. Role of chemerin in the control of glucose homeostasis. Molecular and Cellular Endocrinology 2022 541 111504. (https://doi.org/10.1016/j.mce.2021.111504)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Li L, Ma P, Huang C, Liu Y, Zhang Y, Gao C, Xiao T, Ren PG, Zabel BA, & Zhang JV. Expression of chemerin and its receptors in rat testes and its action on testosterone secretion. Journal of Endocrinology 2014 220 155163. (https://doi.org/10.1530/JOE-13-0275)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Dutta S, & Sengupta P. Men and mice: relating their ages. Life Sciences 2016 152 244248. (https://doi.org/10.1016/j.lfs.2015.10.025)

  • 26

    Ahmadabadi F, Nakhaei H, Mogharnasi M, & Huang CJ. Aerobic interval training improves irisin and chemerin levels of both liver and visceral adipose tissues and circulating asprosin in rats with metabolic syndrome. Physiology International 2021 108 383397. (https://doi.org/10.1556/2060.2021.00182)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Navarro G, Allard C, Xu W, & Mauvais-Jarvis F. The role of androgens in metabolism, obesity, and diabetes in males and females. Obesity 2015 23 713719. (https://doi.org/10.1002/oby.21033)

    • PubMed
    • Search Google Scholar
    • Export Citation