The mitochondrial dicarboxylate carrier prevents hepatic lipotoxicity by inhibiting white adipocyte lipolysis

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

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Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue

Nature Communications ◽

10.1038/s41467-021-22579-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Anastasia Georgiadi ◽

Valeria Lopez-Salazar ◽

Rabih El- Merahbi ◽

Rhoda Anane Karikari ◽

Xiaochuan Ma ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Dependent Manner ◽

Metabolic Dysfunction ◽

Functional Interaction ◽

White Adipocyte ◽

White Adipocytes ◽

Obesity And Diabetes ◽

Adhesion Gpcr ◽

Circulating Levels

AbstractThe proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.

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Cissus Quadrangularis enhances UCP1 mRNA, indicative of white adipocyte browning and decreases central obesity in humans in a randomized trial

Scientific Reports ◽

10.1038/s41598-021-81606-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Saimai Chatree ◽

Chantacha Sitticharoon ◽

Pailin Maikaew ◽

Kitchaya Pongwattanapakin ◽

Issarawan Keadkraichaiwat ◽

...

Keyword(s):

Treated Group ◽

Dependent Manner ◽

Hip Circumference ◽

White Adipocyte ◽

Ppar Γ ◽

White Adipocytes ◽

Cissus Quadrangularis ◽

Baseline Values ◽

Dose Dependent ◽

Vehicle Treated Group

AbstractObesity is associated with the growth and expansion of adipocytes which could be decreased via several mechanisms. Cissus Quadrangularis (CQ) extract has been shown to reduce obesity in humans; however, its effect on human white adipocytes (hWA) has not been elucidated. This study aimed to investigate the effects of CQ on obesity, lipolysis, and browning of hWA. CQ treatment in obese humans significantly decreased waist circumference at week 4 and week 8 when compared with the baseline values (p < 0.05 all) and significantly decreased hip circumference at week 8 when compared with the baseline and week 4 values (p < 0.05 all). Serum leptin levels of the CQ-treated group were significantly higher at week 8 compared to baseline levels (p < 0.05). In hWA, glycerol release was reduced in the CQ-treated group when compared with the vehicle-treated group. In the browning experiment, pioglitazone, the PPAR-γ agonist, increased UCP1 mRNA when compared to vehicle (p < 0.01). Interestingly, 10, 100, and 1000 ng/ml CQ extract treatment on hWA significantly enhanced UCP1 expression in a dose-dependent manner when compared to pioglitazone treatment (p < 0.001 all). In conclusion, CQ decreased waist and hip circumferences in obese humans and enhanced UCP1 mRNA in hWA suggestive of its action via browning of hWA.

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Type 3 Deiodinase Role on Central Thyroid Hormone Action Affects the Leptin-Melanocortin System and Circadian Activity

Endocrinology ◽

10.1210/en.2016-1680 ◽

2016 ◽

Vol 158 (2) ◽

pp. 419-430 ◽

Cited By ~ 11

Author(s):

Zhaofei Wu ◽

M. Elena Martinez ◽

Donald L. St. Germain ◽

Arturo Hernandez

Keyword(s):

Energy Balance ◽

Elevated Serum ◽

Serum Levels ◽

Leptin Resistance ◽

Melanocortin System ◽

White Adipocyte ◽

Pituitary Thyroid Axis ◽

Thyroid Axis ◽

The Central Nervous System ◽

Type 3

Abstract The role of thyroid hormones (THs) in the central regulation of energy balance is increasingly appreciated. Mice lacking the type 3 deiodinase (DIO3), which inactivates TH, have decreased circulating TH levels relative to control mice as a result of defects in the hypothalamic-pituitary-thyroid axis. However, we have shown that the TH status of the adult Dio3−/− brain is opposite that of the serum, exhibiting enhanced levels of TH action. Because the brain, particularly the hypothalamus, harbors important circuitries that regulate metabolism, we aimed to examine the energy balance phenotype of Dio3−/− mice and determine whether it is associated with hypothalamic abnormalities. Here we show that Dio3−/− mice of both sexes exhibit decreased adiposity, reduced brown and white adipocyte size, and enhanced fat loss in response to triiodothyronine (T3) treatment. They also exhibit increased TH action in the hypothalamus, with abnormal expression and T3 sensitivity of genes integral to the leptin-melanocortin system, including Agrp, Npy, Pomc, and Mc4r. The normal to elevated serum levels of leptin, and elevated and repressed expression of Agrp and Pomc, respectively, suggest a profile of leptin resistance. Interestingly, Dio3−/− mice also display elevated locomotor activity and increased energy expenditure. This occurs in association with expanded nighttime activity periods, suggesting a disrupted circadian rhythm. We conclude that DIO3-mediated regulation of TH action in the central nervous system influences multiple critical determinants of energy balance. Those influences may partially compensate each other, with the result likely contributing to the decreased adiposity observed in Dio3−/− mice.

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Limited Mitochondrial Capacity of Visceral Versus Subcutaneous White Adipocytes in Male C57BL/6N Mice

Endocrinology ◽

10.1210/en.2014-1689 ◽

2015 ◽

Vol 156 (3) ◽

pp. 923-933 ◽

Cited By ~ 18

Author(s):

Theresa Schöttl ◽

Lisa Kappler ◽

Katharina Braun ◽

Tobias Fromme ◽

Martin Klingenspor

Keyword(s):

Reactive Oxygen Species ◽

Reactive Oxygen ◽

Mitochondrial Respiratory Chain ◽

Metabolic Risk ◽

Oxygen Species ◽

White Adipocyte ◽

White Adipocytes ◽

Fat Depot ◽

Mitochondrial Capacity

Abstract Accumulation of visceral fat is associated with metabolic risk whereas excessive amounts of peripheral fat are considered less problematic. At the same time, altered white adipocyte mitochondrial bioenergetics has been implicated in the pathogenesis of insulin resistance and type 2 diabetes. We therefore investigated whether the metabolic risk of visceral vs peripheral fat coincides with a difference in mitochondrial capacity of white adipocytes. We assessed bioenergetic parameters of subcutaneous inguinal and visceral epididymal white adipocytes from male C57BL/6N mice employing a comprehensive respirometry setup of intact and permeabilized adipocytes as well as isolated mitochondria. Inguinal adipocytes clearly featured a higher respiratory capacity attributable to increased mitochondrial respiratory chain content compared with epididymal adipocytes. The lower capacity of mitochondria from epididymal adipocytes was accompanied by an increased generation of reactive oxygen species per oxygen consumed. Feeding a high-fat diet (HFD) for 1 week reduced white adipocyte mitochondrial capacity, with stronger effects in epididymal when compared with inguinal adipocytes. This was accompanied by impaired body glucose homeostasis. Therefore, the limited bioenergetic performance combined with the proportionally higher generation of reactive oxygen species of visceral adipocytes could be seen as a candidate mechanism mediating the elevated metabolic risk associated with this fat depot.

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Evaluation of Browning Agents on the White Adipogenesis of Bone Marrow Mesenchymal Stromal Cells: A Contribution to Fighting Obesity

Cells ◽

10.3390/cells10020403 ◽

2021 ◽

Vol 10 (2) ◽

pp. 403

Author(s):

Girolamo Di Maio ◽

Nicola Alessio ◽

Ibrahim Halil Demirsoy ◽

Gianfranco Peluso ◽

Silverio Perrotta ◽

...

Keyword(s):

Bone Marrow ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

White Adipocyte ◽

Drug Candidates ◽

Fat Depots ◽

Treatment Of Obesity ◽

White Fat

Brown-like adipocytes can be induced in white fat depots by a different environmental or drug stimuli, known as “browning” or “beiging”. These brite adipocytes express thermogenin UCP1 protein and show different metabolic advantages, such as the ability to acquire a thermogenic phenotype corresponding to standard brown adipocytes that counteracts obesity. In this research, we evaluated the effects of several browning agents during white adipocyte differentiation of bone marrow-derived mesenchymal stromal cells (MSCs). Our in vitro findings identified two compounds that may warrant further in vivo investigation as possible anti-obesity drugs. We found that rosiglitazone and sildenafil are the most promising drug candidates for a browning treatment of obesity. These drugs are already available on the market for treating diabetes and erectile dysfunction, respectively. Thus, their off-label use may be contemplated, but it must be emphasized that some severe side effects are associated with use of these drugs.

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695 18ß-Glycyrrhetinic Acid Prevents Free Fatty Acid-Induced Hepatic Lipotoxicity by Upregulating GRP78 Expression

Gastroenterology ◽

10.1016/s0016-5085(12)63578-1 ◽

2012 ◽

Vol 142 (5) ◽

pp. S-922 ◽

Cited By ~ 1

Author(s):

Yunzhou Li ◽

Xiaoxuan Zhang ◽

Guangji Wang ◽

Emily C. Gurley ◽

Phillip Hylemon ◽

...

Keyword(s):

Fatty Acid ◽

Free Fatty Acid ◽

Glycyrrhetinic Acid ◽

Hepatic Lipotoxicity

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Role of α1A-adrenoceptor in the regulation of glucose uptake into white adipocyte of rats in vitro

Autonomic Neuroscience ◽

10.1016/s1566-0702(00)00197-1 ◽

2000 ◽

Vol 84 (3) ◽

pp. 140-146 ◽

Cited By ~ 15

Author(s):

Juei-Tang Cheng ◽

I-Min Liu ◽

Shi-Ting Yen ◽

Pei-Chi Chen

Keyword(s):

Glucose Uptake ◽

White Adipocyte

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Magnesium Isoglycyrrhizinate Reduces Hepatic Lipotoxicity through Regulating Metabolic Abnormalities

International Journal of Molecular Sciences ◽

10.3390/ijms22115884 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5884

Author(s):

Li Lu ◽

Kun Hao ◽

Yu Hong ◽

Jie Liu ◽

Jinwei Zhu ◽

...

Keyword(s):

Metabolic Diseases ◽

Lipid Synthesis ◽

Total Lipid Content ◽

Metabolic Activation ◽

Metabolite Profile ◽

Metabolic Enzymes ◽

Antagonistic Effect ◽

Heparg Cells ◽

Hepatic Lipotoxicity ◽

Magnesium Isoglycyrrhizinate

The excessive accumulation of lipids in hepatocytes induces a type of cytotoxicity called hepatic lipotoxicity, which is a fundamental contributor to liver metabolic diseases (such as NAFLD). Magnesium isoglycyrrhizinate (MGIG), a magnesium salt of the stereoisomer of natural glycyrrhizic acid, is widely used as a safe and effective liver protectant. However, the mechanism by which MGIG protects against NAFLD remains unknown. Based on the significant correlation between NAFLD and the reprogramming of liver metabolism, we aimed to explore the beneficial effects of MGIG from a metabolic viewpoint in this paper. We treated HepaRG cells with palmitic acid (PA, a saturated fatty acid of C16:0) to induce lipotoxicity and then evaluated the antagonistic effect of MGIG on lipotoxicity by investigating the cell survival rate, DNA proliferation rate, organelle damage, and endoplasmic reticulum stress (ERS). Metabolomics, lipidomics, and isotope tracing were used to investigate changes in the metabolite profile, lipid profile, and lipid flux in HepaRG cells under different intervention conditions. The results showed that MGIG can indeed protect hepatocytes against PA-induced cytotoxicity and ERS. In response to the metabolic abnormality of lipotoxicity, MGIG curtailed the metabolic activation of lipids induced by PA. The content of total lipids and saturated lipids containing C16:0 chains increased significantly after PA stimulation and then decreased significantly or even returned to normal levels after MGIG intervention. Lipidomic data show that glycerides and glycerophospholipids were the two most affected lipids. For excessive lipid accumulation in hepatocytes, MGIG can downregulate the expression of the metabolic enzymes (GPATs and DAGTs) involved in triglyceride biosynthesis. In conclusion, MGIG has a positive regulatory effect on the metabolic disorders that occur in hepatocytes under lipotoxicity, and the main mechanisms of this effect are in lipid metabolism, including reducing the total lipid content, reducing lipid saturation, inhibiting glyceride and glycerophospholipid metabolism, and downregulating the expression of metabolic enzymes in lipid synthesis.

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Sympathetic Innervation of White Adipose Tissue: to Beige or Not to Beige?

Physiology ◽

10.1152/physiol.00038.2020 ◽

2021 ◽

Vol 36 (4) ◽

pp. 246-255

Author(s):

Heike Münzberg ◽

Elizabeth Floyd ◽

Ji Suk Chang

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Metabolic Regulation ◽

Current Knowledge ◽

Sympathetic Innervation ◽

Neuronal Circuits ◽

Brown Adipocytes ◽

White Adipocyte ◽

Obesity Research ◽

Neuronal Regulation

Obesity research progresses in understanding neuronal circuits and adipocyte biology to regulate metabolism. However, the interface of neuro-adipocyte interaction is less studied. We summarize the current knowledge of adipose tissue innervation and interaction with adipocytes and emphasize adipocyte transitions from white to brown adipocytes and vice versa. We further highlight emerging concepts for the differential neuronal regulation of brown/beige versus white adipocyte and the interdependence of both for metabolic regulation.

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