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Front Endocrinol (Lausanne)
2019 Jan 01;10:750. doi: 10.3389/fendo.2019.00750.
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Melatonin Supplementation Decreases Hypertrophic Obesity and Inflammation Induced by High-Fat Diet in Mice.
de Farias TDSM
,
Cruz MM
,
de Sa RCDC
,
Severi I
,
Perugini J
,
Senzacqua M
,
Cerutti SM
,
Giordano A
,
Cinti S
,
Alonso-Vale MIC
.
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Obesity results from critical periods of positive energy balance characterized by caloric intake greater than energy expenditure. This disbalance promotes adipose tissue dysfunction which is related to other comorbidities. Melatonin is a low-cost therapeutic agent and studies indicate that its use may improve obesity-related disorders. To evaluate if the melatonin is efficient in delaying or even blocking the damages caused by excessive ingestion of a high-fat diet (HFD) in mice, as well as improving the inflammatory profile triggered by obesity herein, male C57BL/6 mice of 8 weeks were induced to obesity by a HFD and treated for 10 weeks with melatonin. The results demonstrate that melatonin supplementation attenuated serum triglyceride levels and total and LDL cholesterol and prevented body mass gain through a decreased lipogenesis rate and increased lipolytic capacity in white adipocytes, with a concomitant increment in oxygen consumption and Pgc1a and Prdm16 expression. Altogether, these effects prevented adipocyte hypertrophy caused by HFD and reflected in decreased adiposity. Finally, melatonin supplementation reduced the crown-like-structure (CLS) formation, characteristic of the inflammatory process by macrophage infiltration into white adipose tissue of obese subjects, as well as decreased the gene expression of inflammation-related factors, such as leptin and MCP1. Thus, the melatonin can be considered a potential therapeutic agent to attenuate the metabolic and inflammatory disorders triggered by obesity.
Figure 1. Effects of high-fat diet (HFD) and melatonin supplementation (Mel, 1 mg/ kg b.w., diluted in drinking water, daily, for 10 weeks) on body weight, food intake, and adiposity. Mice were fed with control diet (Control) or HFD (Obese), supplemented, or not with Mel (Obese+Mel). (A) Changes in body mass (g); (B) Food intake (g/ animal/ day); (C) Food efficiency body weight gain (g)/ food intake (g); (D) Energy efficiency body weight gain (g)/ caloric intake (kcal); Relative weight (mg/ 100 g body weight) of the (E) Subcutaneous adipose depot (inguinal -ING); (F) Visceral adipose depot (epididymal -EPI); (G) Visceral adipose depot (retroperitoneal -RP). (H) Interscapular brown adipose depot (BAT). Results were analyzed by two-way ANOVA and Bonferroni post-test. Values are mean ± SEM (n = 17–21). *P < 0.05 vs. Control; #P <.0.05 vs. Obese.
Figure 2. Effects of high-fat diet (HFD) and melatonin supplementation (Mel, 1 mg/ kg b.w., diluted in drinking water, daily, for 10 weeks) on serum levels of: (A) Triglycerides; (B) Total cholesterol; (C) HDL-cholesterol; and (D) LDL-cholesterol. Mice were fed with control diet (Control) or HFD (Obese), supplemented, or not with Mel (Obese+Mel). Results were analyzed by one-way ANOVA and Tukey post-test. Values are Mean ± SEM (n = 10–12). *P < 0.05 vs. Control.
Figure 3. Effects of high-fat diet (HFD) and melatonin supplementation (Mel, 1 mg/ kg b.w., diluted in drinking water, daily, for 10 weeks) on ING adipocyte morphometry. (A) Adipocyte area of ING adipose depot; (B) Adipocyte volume; (C) ING cellularity; (D) Hematoxylin and eosin (H&E) staining. Mice were fed with control diet (Control) or HFD (Obese), supplemented, or not with Mel (Obese+Mel). Results were analyzed by one-way ANOVA and Tukey post-test. Values are mean ± SEM (n = 17–21 to adipocytes volume and n = 6 to histological analysis). Bar = 100 μm. *P < 0.05 vs. Control; #P < 0.05 vs. Obese.
Figure 4. Effects of high-fat diet (HFD) and melatonin supplementation (Mel, 1 mg/ kg b.w., diluted in drinking water, daily, for 10 weeks) on mRNA levels of genes related to adipogenesis expressed ING adipose tissue. (A) mRNA levels of Ppargama; (B) mRNA levels of C/ebpalfa; (C) mRNA levels of Adiponectin; (D) mRNA levels of Glut-4. 18S was used as the housekeeping gene. Mice were fed with control diet (Control) or HFD (Obese), supplemented, or not with Mel (Obese+Mel). Results were analyzed by one-way ANOVA and Tukey post-test. Values are mean ± SEM (n = 9–13). *P < 0,05 vs. Control; #P < 0,05 vs. Obese.
Figure 5. Effects of high-fat diet (HFD) and melatonin supplementation (Mel, 1 mg/ kg b.w., diluted in drinking water, daily, for 10 weeks) on lipogenesis and lipolysis in ING adipocytes. (A) [1−14]- palmitate incorporation into TGA (nanomoles of incorporated [1−14C]- palmitate per 106 cells); (B) Lipolytic capacity; (C) mRNA levels of Lpl; (D) mRNA levels of Agpat-2;
(E) mRNA levels of Dgat-2;
(F) mRNA levels of Hsl; (G) mRNA levels of Atgl. Mice were fed with control diet (Control) or HFD (Obese), supplemented, or not with Mel (Obese+Mel). Results were analyzed by one-way ANOVA and Tukey post-test. Values are Mean ± SEM (n = 6–8 to metabolic activities and n = 9–13 to gene analysis). *P < 0.05 vs. Control; #P < 0.05 vs. Obese.
Figure 6. Effects of high-fat diet (HFD) and melatonin supplementation (Mel, 1 mg/ kg b.w., diluted in drinking water, daily, for 10 weeks) on oxygen consumption in ING adipocytes. (A) Oxygen consumption; (B) mRNA levels of Pgc1alfa; (C) mRNA levels of Prdm16. Mice were fed with control diet (Control) or HFD (Obese), supplemented, or not with Mel (Obese+Mel). Results were analyzed by one-way ANOVA and Tukey post-test. Results are presented as means ± SEM (n = 8–10). *P < 0.05 vs. Control; #P < 0.05 vs. Obese.
Figure 7. Effects of high-fat diet (HFD) and melatonin supplementation (Mel, 1 mg/ kg b.w., diluted in drinking water, daily, for 10 weeks) on inflammation in the ING depot. Mice were fed with control diet (Control) or HFD (Obese), supplemented, or not with Mel (Obese+Mel). (A) Immunohistochemistry analysis [number of crown-like structures (CLS)/ 10.000 adipocytes] using Mac-2 marker (n = 6). White adipose tissue (WAT) macrophages localize to CLS around individual adipocytes. (B) Light microscopy of inguinal WAT of Control, Obese, and Obese+Mel mice showing MAC-2 immunoreactive macrophages (arrows in brown color). Bar = 100 μm; (C) mRNA levels of Leptin in ING depot; (D) mRNA levels of Il-6 in ING depot; (E) mRNA levels of Mcp-1 in ING depot. Results were analyzed by one-way ANOVA and Tukey post-test. Values are mean ± SEM (n = 9–13). *P < 0.05 vs. Control; #P < 0.05 vs. Obese.
Alonso-Vale,
Adipocyte differentiation is inhibited by melatonin through the regulation of C/EBPbeta transcriptional activity.
2009, Pubmed
Alonso-Vale,
Adipocyte differentiation is inhibited by melatonin through the regulation of C/EBPbeta transcriptional activity.
2009,
Pubmed
Alonso-Vale,
Melatonin and the circadian entrainment of metabolic and hormonal activities in primary isolated adipocytes.
2008,
Pubmed
Alonso-Vale,
Light/dark cycle-dependent metabolic changes in adipose tissue of pinealectomized rats.
2004,
Pubmed
Alonso-Vale,
Intermittent and rhythmic exposure to melatonin in primary cultured adipocytes enhances the insulin and dexamethasone effects on leptin expression.
2006,
Pubmed
Alonso-Vale,
Melatonin enhances leptin expression by rat adipocytes in the presence of insulin.
2005,
Pubmed
Arner,
Genetic predisposition for Type 2 diabetes, but not for overweight/obesity, is associated with a restricted adipogenesis.
2011,
Pubmed
Booth,
Adipose tissue, obesity and adipokines: role in cancer promotion.
2015,
Pubmed
Braun,
Non-adrenergic control of lipolysis and thermogenesis in adipose tissues.
2018,
Pubmed
Camargo,
Effects of Anti-IL-17 on Inflammation, Remodeling, and Oxidative Stress in an Experimental Model of Asthma Exacerbated by LPS.
2017,
Pubmed
Cardinali,
Melatonin, mitochondria, and the metabolic syndrome.
2017,
Pubmed
Cinti,
Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans.
2005,
Pubmed
Cruz,
Palmitoleic acid (16:1n7) increases oxygen consumption, fatty acid oxidation and ATP content in white adipocytes.
2018,
Pubmed
,
Echinobase
Cuesta,
Beneficial effect of melatonin treatment on inflammation, apoptosis and oxidative stress on pancreas of a senescence accelerated mice model.
2011,
Pubmed
Favero,
Melatonin reduces obesity and restores adipokine patterns and metabolism in obese (ob/ob) mice.
2015,
Pubmed
Fried,
Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid.
1998,
Pubmed
Ganie,
Melatonin: A Potential Anti-Oxidant Therapeutic Agent for Mitochondrial Dysfunctions and Related Disorders.
2016,
Pubmed
Gealekman,
Depot-specific differences and insufficient subcutaneous adipose tissue angiogenesis in human obesity.
2011,
Pubmed
Giordano,
Adipose organ nerves revealed by immunohistochemistry.
2008,
Pubmed
Goyal,
Melatonin supplementation to treat the metabolic syndrome: a randomized controlled trial.
2014,
Pubmed
Graham,
Dyslipidemias in the prevention of cardiovascular disease: risks and causality.
2012,
Pubmed
Gray,
Decreased brown adipocyte recruitment and thermogenic capacity in mice with impaired peroxisome proliferator-activated receptor (P465L PPARgamma) function.
2006,
Pubmed
Gustafson,
Restricted adipogenesis in hypertrophic obesity: the role of WISP2, WNT, and BMP4.
2013,
Pubmed
Halberg,
Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue.
2009,
Pubmed
Hardeland,
The significance of the metabolism of the neurohormone melatonin: antioxidative protection and formation of bioactive substances.
1993,
Pubmed
Hotamisligil,
Inflammation and metabolic disorders.
2006,
Pubmed
Hoyos,
Serum cholesterol and lipid peroxidation are decreased by melatonin in diet-induced hypercholesterolemic rats.
2000,
Pubmed
Hussein,
Intake of melatonin is associated with amelioration of physiological changes, both metabolic and morphological pathologies associated with obesity: an animal model.
2007,
Pubmed
Isakson,
Impaired preadipocyte differentiation in human abdominal obesity: role of Wnt, tumor necrosis factor-alpha, and inflammation.
2009,
Pubmed
Jansson,
A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin.
2003,
Pubmed
Jiménez-Aranda,
Melatonin induces browning of inguinal white adipose tissue in Zucker diabetic fatty rats.
2013,
Pubmed
Kaneko,
Obesity alters circadian expressions of molecular clock genes in the brainstem.
2009,
Pubmed
Kang,
Melatonin enhances mitophagy and mitochondrial biogenesis in rats with carbon tetrachloride-induced liver fibrosis.
2016,
Pubmed
Kato,
Melatonin promotes adipogenesis and mitochondrial biogenesis in 3T3-L1 preadipocytes.
2015,
Pubmed
Kireev,
Melatonin is able to prevent the liver of old castrated female rats from oxidative and pro-inflammatory damage.
2008,
Pubmed
Klöting,
Insulin-sensitive obesity.
2010,
Pubmed
Kohsaka,
High-fat diet disrupts behavioral and molecular circadian rhythms in mice.
2007,
Pubmed
Koziróg,
Melatonin treatment improves blood pressure, lipid profile, and parameters of oxidative stress in patients with metabolic syndrome.
2011,
Pubmed
Langin,
Control of fatty acid and glycerol release in adipose tissue lipolysis.
2006,
Pubmed
Lima,
Pinealectomy causes glucose intolerance and decreases adipose cell responsiveness to insulin in rats.
1998,
Pubmed
Liu,
Melatonin reduces intramuscular fat deposition by promoting lipolysis and increasing mitochondrial function.
2019,
Pubmed
Martínez-Martínez,
Leptin induces cardiac fibrosis through galectin-3, mTOR and oxidative stress: potential role in obesity.
2014,
Pubmed
Mesri Alamdari,
A double-blind, placebo-controlled trial related to the effects of melatonin on oxidative stress and inflammatory parameters of obese women.
2015,
Pubmed
Mi,
Melatonin Modulates lipid Metabolism in HepG2 Cells Cultured in High Concentrations of Oleic Acid: AMPK Pathway Activation may Play an Important Role.
2018,
Pubmed
Nduhirabandi,
Short-term melatonin consumption protects the heart of obese rats independent of body weight change and visceral adiposity.
2014,
Pubmed
Otto,
Adipose development: from stem cell to adipocyte.
2005,
Pubmed
Ou,
Melatonin Improves Fatty Liver Syndrome by Inhibiting the Lipogenesis Pathway in Hamsters with High-Fat Diet-Induced Hyperlipidemia.
2019,
Pubmed
Pan,
Melatonin ameliorates nonalcoholic fatty liver induced by high-fat diet in rats.
2006,
Pubmed
Petrovic,
Thermogenically competent nonadrenergic recruitment in brown preadipocytes by a PPARgamma agonist.
2008,
Pubmed
Primeau,
Characterizing the profile of obese patients who are metabolically healthy.
2011,
Pubmed
Prunet-Marcassus,
Melatonin reduces body weight gain in Sprague Dawley rats with diet-induced obesity.
2003,
Pubmed
Quan,
Melatonin inhibits tunicamycin-induced endoplasmic reticulum stress and insulin resistance in skeletal muscle cells.
2015,
Pubmed
Ryu,
Short photoperiod reverses obesity in Siberian hamsters via sympathetically induced lipolysis and Browning in adipose tissue.
2018,
Pubmed
Seale,
Transcriptional control of brown fat determination by PRDM16.
2007,
Pubmed
Shao,
De novo adipocyte differentiation from Pdgfrβ+ preadipocytes protects against pathologic visceral adipose expansion in obesity.
2018,
Pubmed
Sharafati-Chaleshtori,
Melatonin and human mitochondrial diseases.
2017,
Pubmed
She,
NEU-P11, a novel melatonin agonist, inhibits weight gain and improves insulin sensitivity in high-fat/high-sucrose-fed rats.
2009,
Pubmed
Sun,
Adipose tissue remodeling and obesity.
2011,
Pubmed
Szewczyk-Golec,
Inter-relationships of the chronobiotic, melatonin, with leptin and adiponectin: implications for obesity.
2015,
Pubmed
Tan,
Melatonin: A Mitochondrial Targeting Molecule Involving Mitochondrial Protection and Dynamics.
2016,
Pubmed
Teodoro,
Melatonin prevents mitochondrial dysfunction and insulin resistance in rat skeletal muscle.
2014,
Pubmed
Tontonoz,
Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor.
1994,
Pubmed
Wilson-Fritch,
Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone.
2004,
Pubmed
Xu,
Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.
2003,
Pubmed
Yin,
Adipocyte mitochondrial function is reduced in human obesity independent of fat cell size.
2014,
Pubmed
Zanquetta,
Body weight, metabolism and clock genes.
2010,
Pubmed
de Farias,
Pinealectomy interferes with the circadian clock genes expression in white adipose tissue.
2015,
Pubmed
de Sá,
Fish oil prevents changes induced by a high-fat diet on metabolism and adipokine secretion in mice subcutaneous and visceral adipocytes.
2016,
Pubmed
,
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