Obesity and metabolic disorders can be risk factors for neurodegenerative diseases. The content of several lipid species, such as total triglycerides, cholesterol, and ceramides, is elevated in the brains of HFD-fed mice (Charradi et al., 2017). Because dopamine deficiency was observed in obese subjects, the DA system regulates body mass index (Chen et al., 2008). Moreover, DA can reduce glucose uptake in WAT through ARs (Lee et al., 1998). Accordingly, restoring the dopamine level and coactivating dopamine receptors increase protein mass and reduce triglyceride, free fatty acid, and glucose concentrations in the blood (Cincotta et al., 1997). Hypodopaminergic activity was observed in HFD-fed mice; such activity may be involved in the development metabolic syndromes such as hyperlipidemia, hyperglycemia, and insulin intolerance (Fig. 1d, 1e and Fig. 2).
However, GB infusion in BAT restored the DA level, engendered improved glucose homeostasis and insulin sensitivity, and reduced blood triglyceride levels in HFD-fed mice (Fig. 4c–4h and Fig.
5d–5g). Additionally, the midbrain dopaminergic neurons play a pivotal role in reward information processing. Striatal dopaminergic activity was noted to be reduced in depressed patients as compared with controls (Belujon and Grace, 2017). GB infusion in HFD-fed mice caused in an increase in DA levels in the NAc, resulting in relief from depression (Fig. 5a, b).
KATP channels are expressed in catecholaminergic neurons, including the locus coeruleus (LC), which control the sympathetic outflow to BAT (Dunn-Meynell et al., 1998). A previous study
demonstrated that the expression of mutant KATP channels, which are resistant to inhibition by ATP, in the catecholaminergic neurons of the LC reduces the activity of sympathetic nerves in BAT and enhances diet-induced obesity (Tovar et al., 2013). We also found less TH staining in BAT from HFD-fed mice compared with that from chow-fed mice. GB infusion into BAT from HFD-fed mice restored TH fluorescent intensity, resulting in an improved glucose homeostasis, insulin sensitivity, and blood triglyceride concentration (Fig. 6c). Another study demonstrated that the stimulation of KATP channels in the sympathetic nerve endings of the human and guinea pig atrium modulated NE release (Oe et al., 1999). KATP channel closure by GB leads to membrane potential depolarization, in turn increasing sympathetic nerve activity and promoting NE release. Leptin increases the surface expression of KATP channels through adenosine monophosphate–activated protein kinase (AMPK) and PKA in pancreatic β cells to regulate insulin secretion (Chen et al., 2013). As
presented in Fig. 7e and 7f, we speculate that GB increases KATP channels in BAT by promoting NE release for activating β3 AR followed by PKA phosphorylation.
A previous study demonstrated that a bilateral excision of the interscapular BAT in mice at 25°C did not disrupt systemic glucose metabolism, which is a limited thermal stress condition (Grunewald et al., 2018); no apparent failure in sustaining the core temperature when exposed to an environment at 4°C for 24 hours was noted in mice receiving iBATX (Connolly et al., 1982). The water temperature in the forced swim test in the present study was approximately 23°C– 25°C, as suggested in the literature (Can et al., 2012). We observed that mice receiving iBATX exhibited increased immobility in the water tank, which was unlikely due to hypothermia or hypoglycemia (Fig.
3e). Anhedonia is a depressive symptom, and rodents are born with an interest in sweet foods or solutions. Mice receiving iBATX exhibited a decreasing trend of preference for drinking sugar water compared with those that underwent sham surgery (Fig. 3d). We speculate that some mice could be neophobic, having fear of unknown substances; hence, inability of distinguishing anhedonia from fear is a limitation of the sucrose preference test (Serchov et al., 2016). The DA, DOPAC, and 5-HT levels in the NAc were lower in mice that underwent iBATX, supporting the importance of BAT in mood control. The role of BAT in obesity and glucose homeostasis is well established (Poher et
al., 2015; Stanford et al., 2013). Twik-related acid-sensitive potassium channel-1, a pH-sensitive K+ channel, controls thermogenic activity in BAT through β AR signaling (Pisani et al., 2016). KATP
channels not only couple membrane electrical activity to energy metabolism in a variety of cells but also are involved in the pathogenesis of depression. (Esmaeili et al., 2018; Fan et al., 2016).
KATP channels are functionally expressed in BAT, and the inhibition of BAT-KATP channels improves metabolic syndromes and reduces depressive symptoms in HFD-fed mice. Furthermore, we postulate that the closure of BAT-KATP channels induces the release of some endocrine factors from BAT to communicate to the brain. This novel function of BAT-KATP channels emphasizes a previously underappreciated role of BAT in mood control, and manipulating KATP channel levels in BAT can be a possible therapeutic avenue for treating obesity-induced depression (Fig. 8).
Abbrevations
Adenosine triphosphate (ATP)-sensitive K+ (KATP) channels, sulfonylurea receptor 1 (SUR1), brown adipose tissue (BAT), inwardly rectifying potassium channel 6.2 (Kir6.2), glibenclamide (GB), Uncoupling protein 1 (UCP1), white adipose tissue (WAT)
Declarations
Ethical Approval and Consent to participate
The ethical guidelines was approved by the NCKU Animal Care and Use Committee (ethical approval reference number: 106058).
Consent for publication None.
Availability of data and materials
The data that support the findings of this study are available from the corresponding author, PCC, upon reasonable request.
Funding
This research received financial support from the Ministry of Science and Technology (MOST105-2628-B-006-006-MY3, MOST106-2320-B-006-050, and MOST107-2320-B-006-014), offered to Pei-Chun Chen.
Author contributions
YYK contributed to the drafting and design of the study, acquisition of data, and analysis and interpretation of data. JKL, YYK, and YTL contributed to the acquisition and analysis of data. SNW contributed to patch-clamp recording and single-channel analysis. JCC, YMK, and PSC revised the manuscript critically for intellectual content. PCC revised the manuscript, approved the final version to be published, and agreed to be accountable for all the aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Acknowledgments
We thank Dr. Yu-Hua Tseng to provide WT-1 cells at the Joslin Diabetes Center at Harvard Medical School, the staff of the Advanced Light Microscopy Core at National Cheng Kung University Hospital, and Wallace Academic Editing for their help with this manuscript.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Figure legends
Fig. 1: High-fat diet (HFD) feeding for 12 weeks successfully induced metabolic disorders and depressive symptoms. (a) Timeline for animal study, indicating 8-week-old mice were fed either standard diet (chow) or HFD for 12 weeks. During 12th to 14th weeks, mice were subjected to behavioral tests or metabolism-related assays. Tissues were harvested after the fourteenth week.
(b) The body weight of each mouse in the chow or HFD group was measured and averaged. In the third week, HFD-fed mice started exhibiting significant weight gain in comparison with chow-fed mice. (c) Food intake represents average kilocalories consumed per day per mouse in chow- or HFD-fed groups. (d) Glucose tolerance of the mouse groups was compared after fasted mice were challenged with glucose (1.5 g/kg). (e) Insulin tolerance of mouse groups was compared after fasted mice were challenged with insulin (0.75 unit/kg). (f) Representative bar graph indicating effect of chow and HFD on the locomotion distance in the open field test. (g) Representative bar graph indicating effect of chow and HFD on the immobility in the forced swim test before and after acute fluoxetine (FLX, 20 mg/kg) injection. (g) Representative bar graph indicating the intake ratio of sucrose to total intake in sucrose preference test. (Data are presented as means ± SEM; n = 10 per group; *p < 0.05 compared with the chow group; #p < 0.05 compared with the HFD group;
differences are evaluated using either unpaired t-test or one-way analysis of variance and Dunnett’s post hoc test).
Fig. 2: High-fat diet (HFD)-induced obesity resulted in the catecholamine level dysregulation in the nucleus accumbens. (a) Representative bar graphs indicating the catecholamine level in the caudate-putamen. (b) Representative bar graphs indicating the catecholamine level in the nucleus accumbens. (Data are presented as means ± SEM; n = 8 per group; *p < 0.05 compared with the control group; differences are evaluated using unpaired t-test).
Fig. 3: Mice subjected to surgical removal of interscapular brown adipose tissue (iBATX) developed depressive symptoms. (a) Top: Experiment timeline presenting the periods of surgery and indicated tests. Bottom: photographs of the interscapular BAT after sham and iBATX procedures conducted on mice. (b) Average body weight of each mouse. (c) Food intake represented as average kilocalories consumed per day per mouse in the sham or iBATX groups. (d) Representative bar graph indicating the intake ratio of sucrose to total intake in the sucrose preference test. (e) Representative bar graph indicating the effect of sham or iBATX removal surgery on the immobility through the forced swim test. (f-i) Representative bar graphs indicating the catecholamine level in the nucleus accumbens. (Data are presented as means ± SEM; n = 8 per group; *p < 0.05 compared with the control group; differences are evaluated using unpaired t-test).
Fig. 4: Chronic administration of glibenclamide reduced metabolic disorder characteristics without changing body weight and food intake in mice with high-fat diet (HFD)-induced depression. Top:
Timeline indicating the drug regimen. Bodyweight (a) and food intake (b) measured during the 2
weeks of implantation. The detection of the blood glucose level after fasting in glucose- and insulin-challenged mice with glucose tolerance test (GTT) (c) and insulin tolerance test (ITT) (d) tests, respectively. The triglyceride (e), leptin (f), insulin (g), and fasting insulin (h) levels in the four (i.e., chow, HFD, CG, and HG) groups of mice. (Data are presented as means ± SEM; n = 10 per group; *p < 0.05 compared with the control group; #p < 0.05 compared with the HFD group;
differences are evaluated either using one-way or two-way analysis of variance and Dunnett’s post hoc test).
Fig. 5: Chronic administration of glibenclamide attenuated depressive symptoms in high-fat diet (HFD)-induced obese mice. (a) Representative bar graph indicating the intake ratio of sucrose to total intake in sucrose preference test. (b) Representative bar graph indicating the effect of chow or HFD on the immobility in the forced swim test. (c) Representative bar graph indicating the effect of chow or HFD on the locomotion distance in the open field test. Representative bar graphs indicating the catecholamine level, including dopamine (DA) (d), 3,4-dihydroxyphenylacetic acid (DOPAC) (e), DOPAC to DA ratio (f), and serotonin (5-HT) (g), in the nucleus accumbens. (Data are presented as means ± SEM; n = 10 per group; *p < 0.05 compared with the control group; #p <
0.05 compared with the HFD group; differences are evaluated using one-way analysis of variance and Dunnett’s post hoc test).
Fig. 6: Chronic administration of glibenclamide (GB) affected the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel expression in the interscapular brown adipose tissue. (a) Top: Representative blotting images indicating the levels of sulfonylurea receptor 1 (SUR1),
potassium pore-forming (Kir6.2), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in the four (i.e., chow, high-fat diet [HFD], chow + GB [CG], and HFD + GB [HG]) groups of mice. Bottom:
Representative bar graph indicating the SUR1 to Kir6.2 ratio. (b) Immunofluorescence staining of the paraffin embedded BAT sections from the four groups of mice with SUR1 (green) and Kir6.2 (red) antibodies. The scale bar is 100 µm. (c) Immunohistochemistry analysis of the paraffin embedded BAT sections from the four groups of mice using tyrosine hydroxylase antibody. The signal for TH is dark brown. The scale bar is 100 µm. (Data are presented as means ± SEM; n = 10 per group; *p < 0.05 compared with the control group; #p < 0.05 compared with the HFD group;
differences are evaluated using one-way analysis of variance and Dunnett’s post hoc test).
Fig. 7: Examination of KATP channels in differentiated primary brown adipocytes and WT-1 cell line.
(a) Representative blotting images indicating the presence of sulfonylurea receptor 1 (SUR1), potassium pore-forming (Kir6.2), and Uncoupling protein 1 (UCP1) proteins in the differentiated primary brown (BAT), but not in the white adipocytes (WAT). (b) The morphological examination by
immunofluorescence staining using UCP1 antibody (green) and DAPI for staining of nucleus. of primary brown and white adipocytes culture treated with beta-3-adrenergic receptors (β3 ARs)
agonist for 3, 5, and 7 days. The scale bar is 100 µm. (c) The electrophysiological recording
presenting the KATP channel current in the primary brown adipocytes. This current was increased by diazoxide and inhibited by glibenclamide. (d) Top: Differentiated primary brown adipocytes treated with β3 AR agonist for 7 days and subjected to immunostaining for SUR1 protein (red). Bottom:
Representative bar graph indicating the quantification of the immunofluorescence intensity of SUR1 protein. The scale bar is 10 µm. (e) Representative bar graph indicating the relative expression of SUR1, Kir6.2, and UCP1 proteins in undifferentiated and differentiated WT-1 cells. (Data are presented as means ± SEM; n = 8 per group; *p < 0.05 compared with the corresponding undifferentiated group). (f) Top: Representative blotting images indicating the SUR1 level after WT-1 cells were treated with various indicated drugs. Bottom: Representative bar graph indicating
the changes in SUR1 expression after drug treatments. (Data are presented as means ± SEM; n = 3 per group; *p < 0.05 compared with the vehicle-treated group; #p < 0.05 compared with the β3 AR agonist-treated (for 30 minutes) group; $p < 0.05 compared with the β3 AR agonist-treated (60
minutes) group; differences are evaluated using one-way ANOVA and Dunnett’s post hoc test).
Fig. 8: Schematic of glibenclamide-increased KATP channel expression in BAT. GB infusion recovered activities of sympathetic nerves by closing KATP channels to stimulate depolarization, in turn increasing norepinephrine (NE) release. NE bound to beta-3-adrenergic receptors activated protein kinase A phosphorylation and promoted trafficking of KATP channels. GB served as the chemical chaperone for assisting the KATP channel folding. Overall, more KATP channels were
expressed in brown adipocytes. The other function of GB is to close KATP channels, possibly inducing some endocrine factors released from brown adipose tissue to exert anti-depression.
Supplementary Fig. 1: High-fat diet (HFD) feeding for 12 weeks successfully induced metabolic disorders and depressive symptoms. (a) Timeline for animal study, indicating 8-week-old mice were fed either standard diet (chow) or HFD for 12 weeks. During 12th to 14th weeks, mice were subjected to behavioral tests or metabolism-related assays. Tissues were harvested after the fourteenth week. (b) The body weight of each mouse in the chow or HFD group was measured and averaged. In the third week, HFD-fed mice started exhibiting significant weight gain in comparison with chow-fed mice. (c) Food intake represents average kilocalories consumed per day per mouse in chow- or HFD-fed groups. (d) Glucose tolerance of the mouse groups was compared after fasted mice were challenged with glucose (1.5 g/kg). (e) Insulin tolerance of mouse groups was compared after fasted mice were challenged with insulin (0.75 unit/kg). (f) Representative bar graph indicating effect of chow and HFD on the locomotion distance in the open field test. (g) Representative bar graph indicating effect of chow and HFD on the immobility in the forced swim test before and after acute fluoxetine (FLX, 20 mg/kg) injection. (g) Representative bar graph indicating the intake ratio of sucrose to total intake in sucrose preference test. (Data are presented as means ± SEM; n = 10 per group; *p < 0.05 compared with the chow group; #p < 0.05 compared with the HFD group;
differences are evaluated using either unpaired t-test or one-way analysis of variance and Dunnett’s post hoc test).
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