Lack of monoacylglycerol lipase prevents hepatic steatosis by favoring lipid storage in adipose tissue and intestinal malabsorption

IntroductionExercise training has been shown to be the most effective strategy to combat obesity and non-alcoholic fatty liver disease. However, exercise promotes loss of adipose tissue mass and improves obesity-related hepatic steatosis through mechanisms that remain obscure.Research design and methodsTo study the role of interleukin-6 (IL-6) in high-fat diet (HFD)-induced adiposity and hepatic steatosis during treadmill running, IL-6 knockout (IL-6 KO) mice and wild-type (WT) mice were randomly divided into lean, obese (fed a HFD) and trained obese groups (fed a HFD and exercise trained).ResultsAfter 20 weeks of HFD feeding and 8 weeks of treadmill running, we found that exercise obviously reduced HFD-induced body weight gain, inhibited visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) expansion and almost completely reversed obesity-related intrahepatic fat accumulation in WT mice. However, IL-6 knockout (IL-6 KO) mice are refractory to the benefits of treadmill training on body weight, VAT and SAT mass elevation, and hepatic steatosis. Moreover, a panel of lipolytic-related and thermogenic-related genes, including ATGL, HSL and PGC-1α, was upregulated in the VAT and SAT of WT mice that received exercise training compared with untrained mice, which was not observed in IL-6 KO mice. In addition, exercise training resulted in a significant inhibition of hepatic peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in WT mice, and these effects were not noted in IL-6 KO mice.ConclusionThese results revealed that IL-6 is involved in the prevention of obesity and hepatic fat accumulation during exercise training. The mechanisms underlying these antiobesity effects may be associated with enhanced lipolysis and thermogenesis in white adipose tissue. The improvement in hepatic steatosis by exercise training may benefit from the marked inhibition of PPAR-γ expression by IL-6.

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Xylo-Oligosaccharides in Prevention of Hepatic Steatosis and Adipose Tissue Inflammation: Associating Taxonomic and Metabolomic Patterns in Fecal Microbiomes with Biclustering

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18084049 ◽

2021 ◽

Vol 18 (8) ◽

pp. 4049

Author(s):

Jukka Hintikka ◽

Sanna Lensu ◽

Elina Mäkinen ◽

Sira Karvinen ◽

Marjaana Honkanen ◽

...

Keyword(s):

Amino Acids ◽

Adipose Tissue ◽

Hepatic Steatosis ◽

Insulin Signaling ◽

Aromatic Amino Acids ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Beneficial Effects ◽

Male Wistar Rats ◽

Branched Chain

We have shown that prebiotic xylo-oligosaccharides (XOS) increased beneficial gut microbiota (GM) and prevented high fat diet-induced hepatic steatosis, but the mechanisms associated with these effects are not clear. We studied whether XOS affects adipose tissue inflammation and insulin signaling, and whether the GM and fecal metabolome explain associated patterns. XOS was supplemented or not with high (HFD) or low (LFD) fat diet for 12 weeks in male Wistar rats (n = 10/group). Previously analyzed GM and fecal metabolites were biclustered to reduce data dimensionality and identify interpretable groups of co-occurring genera and metabolites. Based on our findings, biclustering provides a useful algorithmic method for capturing such joint signatures. On the HFD, XOS-supplemented rats showed lower number of adipose tissue crown-like structures, increased phosphorylation of AKT in liver and adipose tissue as well as lower expression of hepatic miRNAs. XOS-supplemented rats had more fecal glycine and less hypoxanthine, isovalerate, branched chain amino acids and aromatic amino acids. Several bacterial genera were associated with the metabolic signatures. In conclusion, the beneficial effects of XOS on hepatic steatosis involved decreased adipose tissue inflammation and likely improved insulin signaling, which were further associated with fecal metabolites and GM.

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Vascular Adhesion Protein 1 Mediates Gut Microbial Flagellin-Induced Inflammation, Leukocyte Infiltration, and Hepatic Steatosis

Sci ◽

10.3390/sci3010013 ◽

2021 ◽

Vol 3 (1) ◽

pp. 13

Author(s):

Raine Toivonen ◽

Sanja Vanhatalo ◽

Maija Hollmén ◽

Eveliina Munukka ◽

Anniina Keskitalo ◽

...

Keyword(s):

Adipose Tissue ◽

Hepatic Steatosis ◽

Visceral Adipose Tissue ◽

Leukocyte Infiltration ◽

Fat Accumulation ◽

Adhesion Protein ◽

Hepatic Fat ◽

Vascular Adhesion ◽

Visceral Adipose ◽

Vascular Adhesion Protein 1

Toll-like receptor 5 ligand, flagellin, and vascular adhesion protein 1 (VAP-1) are involved in non-alcoholic fatty liver disease. This study aimed to determine whether VAP-1 mediates flagellin-induced hepatic fat accumulation. The effects of flagellin on adipocyte VAP-1 expression were first studied in vitro. Then, flagellin (100 ng/mouse) or saline was intraperitoneally injected into C57BL/6J (WT) and C57BL/6-Aoc3-/- (VAP-1 KO) mice on a high-fat diet twice a week every 2 weeks for 10 weeks. After that, the effects on inflammation, insulin signaling, and metabolism were studied in liver and adipose tissues. Hepatic fat was quantified histologically and biochemically. Because flagellin challenge increased VAP-1 expression in human adipocytes, we used VAP-1 KO mice to determine whether VAP-1 regulates the inflammatory and metabolic effects of flagellin in vivo. In mice, VAP-1 mediated flagellin-induced inflammation, leukocyte infiltration, and lipolysis in visceral adipose tissue. Consequently, an increased release of glycerol led to hepatic steatosis in WT, but not in KO mice. Flagellin-induced hepatic fibrosis was not mediated by VAP-1. VAP-1 KO mice harbored more inflammation-related microbes than WT mice, while flagellin did not affect the gut microbiota. Our results suggest that by acting on visceral adipose tissue, flagellin increased leukocyte infiltration that induced lipolysis. Further, the released glycerol participated in hepatic fat accumulation. In conclusion, the results describe that gut microbial flagellin through VAP-1 induced hepatic steatosis.

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Expression Signatures of microRNAs and Their Targeted Pathways in the Adipose Tissue of Chickens during the Transition from Embryonic to Post-Hatch Development

Genes ◽

10.3390/genes12020196 ◽

2021 ◽

Vol 12 (2) ◽

pp. 196

Author(s):

Julie A. Hicks ◽

Hsiao-Ching Liu

Keyword(s):

Energy Source ◽

Adipose Tissue ◽

De Novo ◽

Lipid Storage ◽

Storage Site ◽

Metabolic Processes ◽

Metabolic Switch ◽

Regulatory Pathways ◽

Main Site ◽

Real Time Quantitative Pcr

As the chick transitions from embryonic to post-hatching life, its metabolism must quickly undergo a dramatic switch in its major energy source. The chick embryo derives most of its energy from the yolk, a lipid-rich/carbohydrate-poor source. Upon hatching, the chick’s metabolism must then be able to utilize a lipid-poor/carbohydrate-rich source (feed) as its main form of energy. We recently found that a number of hepatically-expressed microRNAs (miRNAs) help facilitate this shift in metabolic processes in the chick liver, the main site of lipogenesis. While adipose tissue was initially thought to mainly serve as a lipid storage site, it is now known to carry many metabolic, endocrine, and immunological functions. Therefore, it would be expected that adipose tissue is also an important factor in the metabolic switch. To that end, we used next generation sequencing (NGS) and real-time quantitative PCR (RT-qPCR) to generate miRNome and transcriptome signatures of the adipose tissue during the transition from late embryonic to early post-hatch development. As adipose tissue is well known to produce inflammatory and other immune factors, we used SPF white leghorns to generate the initial miRNome and transcriptome signatures to minimize complications from external factors (e.g., pathogenic infections) and ensure the identification of bona fide switch-associated miRNAs and transcripts. We then examined their expression signatures in the adipose tissue of broilers (Ross 708). Using E18 embryos as representative of pre-switching metabolism and D3 chicks as a representative of post-switching metabolism, we identified a group of miRNAs which work concordantly to regulate a diverse but interconnected group of developmental, immune and metabolic processes in the adipose tissue during the metabolic switch. Network mapping suggests that during the first days post-hatch, despite the consumption of feed, the chick is still heavily reliant upon adipose tissue lipid stores for energy production, and is not yet efficiently using their new energy source for de novo lipid storage. A number of core master regulatory pathways including, circadian rhythm transcriptional regulation and growth hormone (GH) signaling, likely work in concert with miRNAs to maintain an essential balance between adipogenic, lipolytic, developmental, and immunological processes in the adipose tissue during the metabolic switch.

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ROLE OF MONOACYLGLYCEROL LIPASE IN ADIPOSE TISSUE METABOLISM

Biochemical Society Transactions ◽

10.1042/bst009185pb ◽

1981 ◽

Vol 9 (2) ◽

pp. 185P-185P

Author(s):

Hans Tornqvist

Keyword(s):

Adipose Tissue ◽

Monoacylglycerol Lipase ◽

Adipose Tissue Metabolism ◽

Tissue Metabolism

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Edible Red Seaweed Campylaephora Hypnaeoides J. Agardh Alleviates Obesity and Related Metabolic Disorders in Mice by Suppressing Oxidative Stress and Inflammatory Response

10.21203/rs.3.rs-877916/v1 ◽

2021 ◽

Author(s):

Shigeru Murakami ◽

Chihiro Hirazawa ◽

Rina Yoshikawa ◽

Toshiki Mizutani ◽

Takuma Ohya ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Hepatic Steatosis ◽

White Adipose Tissue ◽

Metabolic Disorders ◽

Public Health Problem ◽

Serum Levels ◽

Diet Group ◽

Raw264.7 Cells ◽

Edible Seaweed

Abstract Background: The obesity epidemic has become a serious public health problem in many countries worldwide. Seaweed has few calories and is rich in active nutritional components necessary for health promotion and disease prevention. The aim of this study was to investigate the effects of the Campylaephora hypnaeoides J. Agardh (C. hypnaeoides), an edible seaweed traditionally eaten in Japan, on high-fat (HF) diet-induced obesity and related metabolic diseases in mice.Methods: Male C57BL/6J mice were randomly divided into the following groups: normal diet group, HF diet group, HF diet supplemented with 2% C. hypnaeoides, and HF diet supplemented with 6% C. hypnaeoides. After 13 weeks of treatment, the weight of the white adipose tissue and liver, and the serum levels of glucose, insulin, adipokines, and lipids were measured. Hepatic levels of adipokines, oxidant markers, and antioxidant markers were also determined. Insulin resistance was assessed by a glucose tolerance test. Polysaccharides of C. hypnaeoides were purified and their molecular weight was determined by high-performance seize exclusion chromatography. The anti-inflammatory effects of purified polysaccharides were evaluated in RAW264.7 cells. Results: Treatment of HF diet-induced obese mice with C. hypnaeoides for 13 weeks suppressed the increase in body weight and white adipose tissue weight. It also ameliorated insulin resistance, diabetes, hepatic steatosis, and hypercholesterolemia. The ingestion of an HF diet increased serum levels of malondialdehyde (MDA), tumor necrosis factor a (TNF-a), and monocyte chemoattractant protein-1 (MCP-1), while it decreased serum adiponectin levels. In the liver, an HF diet markedly increased the MDA, TNF-a, and interleukin-6 (IL-6) levels, while it decreased glutathione (GSH) and superoxide dismutase (SOD). These metabolic changes induced by HF diet feeding were ameliorated by dietary C. hypnaeoides. Purified polysaccharides and ethanol extract from C. hypnaeoides inhibited the lipopolysaccharide-induced overproduction of nitric oxide and TNF-a in macrophage RAW264.7 cells. Conclusions: The present results indicated that C. hypnaeoides was able to alleviate HF diet-induced metabolic disorders, including obesity, diabetes, hepatic steatosis, and hypercholesterolemia by attenuating inflammation and improving the antioxidant capacity in mice. Polysaccharides and polyphenols may be involved in these beneficial effects of C. hypnaeoides.

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Corticosterone decreases nonshivering thermogenesis and increases lipid storage in brown adipose tissue

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1995.268.1.r183 ◽

1995 ◽

Vol 268 (1) ◽

pp. R183-R191 ◽

Cited By ~ 13

Author(s):

A. M. Strack ◽

M. J. Bradbury ◽

M. F. Dallman

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Glucocorticoid Receptors ◽

Uncoupling Protein ◽

Lipid Storage ◽

Scatchard Analysis ◽

Nonshivering Thermogenesis ◽

Diurnal Range ◽

Brown Adipose ◽

Intact Rats

Brown adipose tissue (BAT) contains glucocorticoid receptors; glucocorticoids are required for maintaining differentiated BAT in culture. These studies were performed to determine the effects of corticosterone on BAT thermogenic function and lipid storage. Rats were adrenalectomized and given subcutaneous corticosterone pellets in concentrations that maintained plasma corticosterone constant across the range of 0-20 micrograms/dl or were sham adrenalectomized. All variables were examined 5 days after surgery and corticosterone replacement. Measures of BAT function-thermogenic capacity [guanosine 5'-diphosphate (GDP) binding and uncoupling protein (UCP; a BAT-specific thermogenic protein)] and storage (BAT wet wt, protein, and DNA levels) were made. Plasma hormones (corticosterone, adrenocorticotropic hormone, insulin, 3,3',5-triiodothyronine, and thyroxine were measured. Corticosterone significantly affected BAT thermogenic measures: UCP content and binding of GDP to BAT mitochondria decreased with increasing corticosterone; GDP binding characteristics in BAT from similarly prepared rats examined by Scatchard analysis showed that maximum binding (Bmax) and dissociation constant (Kd) decreased with increasing corticosterone dose. BAT DNA was increased by adrenalectomy and maintained at intact levels with all doses of corticosterone; BAT lipid storage increased dramatically at corticosterone values higher than the daily mean level in intact rats. Histologically, the number and size of lipid droplets within BAT adipocytes increased markedly with increased corticosterone. White adipose depots were more sensitive to circulating corticosterone concentrations than were BAT depots and increased in weight at levels of corticosterone that were at or below the daily mean level of intact rats. We conclude that, within its diurnal range of concentration corticosterone acts to inhibit nonshivering thermogenesis and increase lipid storage.(ABSTRACT TRUNCATED AT 250 WORDS)

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Ubc9 deletion in adipocytes causes lipoatrophy in mice

10.1101/2020.09.12.294629 ◽

2020 ◽

Author(s):

Aaron R. Cox ◽

Natasha Chernis ◽

Kang Ho Kim ◽

Peter M. Masschelin ◽

Pradip K. Saha ◽

...

Keyword(s):

Adipose Tissue ◽

Energy Balance ◽

Hepatic Steatosis ◽

Postnatal Growth ◽

Endocrine Control ◽

Brown Adipocytes ◽

Human Adipocyte ◽

White Adipocyte ◽

Adipose Tissue Depots

ABSTRACTObjectiveWhite adipose tissue (WAT) expansion regulates energy balance and overall metabolic homeostasis. WAT absence or loss occurring through lipodystrophy and lipoatrophy contributes to the development of dyslipidemia, hepatic steatosis, and insulin resistance. We previously demonstrated the sole small ubiquitin-like modifier (SUMO) E2-conjuguating enzyme Ubc9 represses human adipocyte differentiation. Germline and other tissue-specific deletions of Ubc9 frequently cause lethality in mice. As a result, the role of Ubc9 during WAT development remains unknown.MethodsTo determine how Ubc9 impacts body composition and energy balance, we generated adipocyte-specific Ubc9 knockout mice (Ubc9a-KO). CRISPR/Cas9 gene editing inserted loxP sites flanking exons 3 and 4 at the Ubc9 locus. Subsequent genetic crosses to AdipoQ-Cre transgenic mice allowed deletion of Ubc9 in white and brown adipocytes. We measured multiple metabolic endpoints that describe energy balance and carbohydrate metabolism in Ubc9a-KO and littermate controls during postnatal growth.ResultsTo our surprise, Ubc9a-KO mice developed hyperinsulinemia and hepatic steatosis. Global energy balance defects emerged from dysfunctional WAT marked by pronounced local inflammation, loss of serum adipokines, hepatomegaly, and near absence of major adipose tissue depots. We observed progressive lipoatrophy that commences in the early adolescent period.ConclusionsOur results demonstrate that Ubc9 expression in mature adipocytes is essential for maintaining WAT expansion. Deletion of Ubc9 in fat cells compromised and diminished adipocyte function that provoked WAT inflammation and ectopic lipid accumulation in the liver. Our findings reveal an indispensable role for Ubc9 during white adipocyte expansion and endocrine control of energy balance.

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