Deficiency of Cathelicidin Attenuates High-Fat Diet Plus Alcohol-Induced Liver Injury through FGF21/Adiponectin Regulation

Alcohol consumption and obesity are known risk factors of steatohepatitis. Here, we report that the deficiency of CRAMP (cathelicidin-related antimicrobial peptide—gene name: Camp) is protective against a high-fat diet (HFD) plus acute alcohol (HFDE)-induced liver injury. HFDE markedly induced liver injury and steatosis in WT mice, which were attenuated in Camp–/– mice. Neutrophil infiltration was lessened in the liver of Camp–/– mice. HFDE feeding dramatically increased epididymal white adipose tissue (eWAT) mass and induced adipocyte hypertrophy in WT mice, whereas these effects were attenuated by the deletion of Camp. Furthermore, Camp–/– mice had significantly increased eWAT lipolysis, evidenced by up-regulated expression of lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL). The depletion of Camp also increased uncoupling protein 1 (UCP1)-dependent thermogenesis in the brown adipose tissue (BAT) of mice. HFDE fed Camp–/– mice had elevated protein levels of fibroblast growth factor 21 (FGF21) in the eWAT, with an increased adiponectin production, which had been shown to alleviate hepatic fat deposition and inflammation. Collectively, we have demonstrated that Camp–/– mice are protected against HFD plus alcohol-induced liver injury and steatosis through FGF21/adiponectin regulation. Targeting CRAMP could be an effective approach for prevention/treatment of high-fat diet plus alcohol consumption-induced steatohepatitis.

Download Full-text

The Crude Extract fromPuerariaeFlower Exerts Antiobesity and Antifatty Liver Effects in High-Fat Diet-Induced Obese Mice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/272710 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

Tomoyasu Kamiya ◽

Mayu Sameshima-Kamiya ◽

Rika Nagamine ◽

Masahito Tsubata ◽

Motoya Ikeguchi ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Uncoupling Protein ◽

Expression Profiles ◽

Folk Medicine ◽

Hormone Sensitive Lipase ◽

Leguminous Plant ◽

Obese Mice ◽

High Fat ◽

Brown Adipose

Kudzu, a leguminous plant, has long been used in folk medicine. In particular, its flowers are used in Japanese and Chinese folk medicine for treating hangovers. We focused on the flower of Kudzu (Puerariae thomsonii), and we previously reported the antiobesity effect ofPuerariae thomsoniiflower extract (PFE) in humans. In this study, we conducted an animal study to investigate the effect of PFE on visceral fat and hepatic lipid levels in mice with diet-induced obesity. In addition, we focused on gene expression profiles to investigate the antiobesity mechanism of PFE. Male C57BL/6J mice were fed a high-fat diet (HFD) or an HFD supplemented with 5% PFE for 14 days. PFE supplementation significantly reduced body weight and white adipose tissue (WAT) weight. Moreover, in the histological analysis, PFE supplementation improved fatty liver. Hepatic reverse transcription-polymerase chain reaction revealed that PFE supplementation downregulated acetyl-CoA carboxylase expression. For adipose tissue, the expressions of hormone-sensitive lipase in WAT and uncoupling protein 1 in brown adipose tissue (BAT) were significantly upregulated. These results suggest that PFE exerts antiobesity and antifatty liver effects in high-fat diet-induced obese mice through suppressing lipogenesis in the liver, stimulating lipolysis in WAT, and promoting thermogenesis in BAT.

Download Full-text

Thyroxine 5'-deiodinase in brown adipose tissue of myopathic hamsters

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1986.251.1.e8 ◽

1986 ◽

Vol 251 (1) ◽

pp. E8-E13 ◽

Cited By ~ 1

Author(s):

J. Kopecky ◽

L. Sigurdson ◽

I. R. Park ◽

J. Himms-Hagen

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

High Fat Diet ◽

Uncoupling Protein ◽

High Fat ◽

Mitochondrial Uncoupling ◽

Mitochondrial Uncoupling Protein ◽

Endogenous Production ◽

Deiodinase Activity ◽

Brown Adipose

Myopathic Syrian hamsters (BIO 14.6) have less brown adipose tissue (BAT) than normal. The trophic response of this tissue to cold is smaller than normal and trophic responses to diet and to photoperiod are absent. The objective was to find out whether activity of thyroxine 5'-deiodinase in their BAT was increased normally in response to cold and thus whether a defect in endogenous production of 3,5,3'-triiodothyronine might underlie the attenuated trophic response. The effect of feeding a high-fat diet on activity of 5'-deiodinase was also studied. Cold acclimation increased thyroxine 5'-deiodinase activity in BAT of the myopathic hamster, but the total remained smaller than normal because of the smaller size. The cold-induced increase in concentration of mitochondrial uncoupling protein was also smaller than normal. The level of serum 3,5,3'-triiodothyronine was low in myopathic hamsters and remained lower than normal when they were cold-exposed or cold acclimated. Feeding the high-fat diet to myopathic hamsters resulted in a greater than normal suppression of thyroxine 5'-deiodinase activity than in normal hamsters; the normal increases in protein content and in concentration of mitochondrial uncoupling protein were absent. We conclude that the defective trophic response of BAT of the myopathic hamster is not secondary to defective regulation of its thyroxine 5'-deiodinase activity because this activity does not appear to be obligatorily linked to hypertrophy of BAT. The low level of serum 3,5,3'-triiodothyronine in the myopathic hamster may be secondary to reduced capacity for peripheral thyroxine deiodination in its BAT.

Download Full-text

Pathological Conversion of Mouse Perivascular Adipose Tissue by Notch Activation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314731 ◽

2020 ◽

Vol 40 (9) ◽

pp. 2227-2243 ◽

Cited By ~ 1

Author(s):

Joshua M. Boucher ◽

Larisa Ryzhova ◽

Anne Harrington ◽

Jessica Davis-Knowlton ◽

Jacqueline E. Turner ◽

...

Keyword(s):

Adipose Tissue ◽

Notch Signaling ◽

High Fat Diet ◽

Vascular Function ◽

Uncoupling Protein ◽

Standard Diet ◽

Lipid Deposition ◽

High Fat ◽

Perivascular Adipose Tissue ◽

Brown Adipose

Objective: Perivascular adipose tissue (PVAT) surrounding arteries supports healthy vascular function. During obesity, PVAT loses its vasoprotective effect. We study pathological conversion of PVAT, which involves molecular changes in protein profiles and functional changes in adipocytes. Approach and Results: C57BL6/J mice were fed a 60% high-fat diet for 12 weeks or a cardioprotective 30% calorie-restricted diet for 5 weeks. Proteomic analysis identified PVAT as a molecularly distinct adipose depot, and novel markers for thermogenic adipocytes, such as GRP75 (stress-70 protein, mitochondrial), were identified. High-fat diet increased the similarity of protein signatures in PVAT and brown adipose, suggesting activation of a conserved whitening pathway. The whitening phenotype was characterized by suppression of UCP1 (uncoupling protein 1) and increased lipid deposition, leptin, and inflammation, and specifically in PVAT, elevated Notch signaling. Conversely, PVAT from calorie-restricted mice had decreased Notch signaling and less lipid. Using the Adipoq-Cre strain, we constitutively activated Notch1 signaling in adipocytes, which phenocopied the changes in PVAT caused by a high-fat diet, even on a standard diet. Preadipocytes from mouse PVAT expressed Sca1, CD140a, Notch1, and Notch2, but not CD105, showing differences compared with preadipocytes from other depots. Inhibition of Notch signaling during differentiation of PVAT-derived preadipocytes reduced lipid deposition and adipocyte marker expression. Conclusions: PVAT shares features with other adipose depots, but has a unique protein signature that is regulated by dietary stress. Increased Notch signaling in PVAT is sufficient to initiate the pathological conversion of PVAT by promoting adipogenesis and lipid accumulation and may thus prime the microenvironment for vascular disease.

Download Full-text

Cranberry Polyphenolic Extract Exhibits an Antiobesity Effect on High-Fat Diet–Fed Mice through Increased Thermogenesis

Journal of Nutrition ◽

10.1093/jn/nxaa163 ◽

2020 ◽

Vol 150 (8) ◽

pp. 2131-2138 ◽

Cited By ~ 1

Author(s):

Fang Zhou ◽

Jielong Guo ◽

Xue Han ◽

Yunxiao Gao ◽

Qimin Chen ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

High Fat Diet ◽

Body Weight Gain ◽

Uncoupling Protein ◽

The Body ◽

High Fat ◽

Uncoupling Protein 1 ◽

Polyphenolic Extract ◽

Brown Adipose

ABSTRACT Background Although polyphenol-rich cranberry extracts reportedly have an antiobesity effect, the exact reason for this remains unclear. Objectives In light of the reported health benefits of the polyphenolic compounds in cranberry, we investigated the effects and mechanism of a cranberry polyphenolic extract (CPE) in high-fat diet (HFD)–fed obese mice. Methods The distributions of individual CPE compounds were characterized by HPLC fingerprinting. Male C57BL/6J mice (4 wk old) were fed for 16 wk normal diet (ND, 10% fat energy) or HFD (60% fat energy) with or without 0.75% CPE in drinking water (HFD + CPE). Body and adipose depot weights, indices of glucose metabolism, energy expenditure (EE), and expression of genes related to brown adipose tissue (BAT) thermogenesis, and inguinal/epididymal white adipose tissue (iWAT/eWAT) browning were measured. Results After 16 wk, the body weight was 22.5% lower in the CPE-treated mice than in the HFD group but remained 17.9% higher than in the ND group. CPE treatment significantly increased EE compared with that of the ND and HFD groups. The elevated EE was linked with BAT thermogenesis, and iWAT/eWAT browning, shown by the induction of thermogenic genes, especially uncoupling protein 1 (Ucp1), and browning-related genes, including Cd137, a member of the tumor necrosis factor receptor superfamily (Tnfrsf9). The mRNA expression and abundance of uncoupling protein 1 in BAT of CPE-fed mice were 5.78 and 1.47 times higher than in the HFD group, and 0.61 and 1.12 times higher than in the ND group, respectively. Cd137 gene expression in iWAT and eWAT of CPE-fed mice were 2.35 and 3.13 times higher than in the HFD group, and 0.84 and 1.39 times higher than in the ND group, respectively. Conclusions Dietary CPE reduced but did not normalize HFD-induced body weight gain in male C57BL/6J mice, possibly by affecting energy metabolism.

Download Full-text

Control of norepinephrine turnover in brown adipose tissue of Syrian hamsters

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1988.254.6.r960 ◽

1988 ◽

Vol 254 (6) ◽

pp. R960-R968

Author(s):

S. L. Sigurdson ◽

J. Himms-Hagen

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

High Fat Diet ◽

Uncoupling Protein ◽

Short Photoperiod ◽

High Fat ◽

Syrian Hamsters ◽

Norepinephrine Turnover ◽

Low T3 ◽

Brown Adipose

Sympathetic nervous system activity in brown adipose tissue (BAT) of normal and myopathic Syrian hamsters was assessed by measuring norepinephrine turnover rate (NETR) using [3H]norepinephrine. Acute exposure of normal hamsters to cold (4 degrees C) for 4 or 24 h increased norepinephrine secretion but not resynthesis. By 3 days and at 2 wk in the cold, NETR increased but returned to a normal level by 6 wk. Hamsters were initially hypothermic (to 3 days) then normothermic (2 and 6 wk). Adaptation of normal or myopathic hamsters to high-fat diet or short photoperiod (4 h light, 20 h dark) for up to 12 wk did not alter NETR in BAT. Serum triiodothyronine (T3) concentration increased rapidly in the cold to reach a maximum level by 24 h at which it remained for 6 wk and was not correlated with changes in NETR in BAT. The high-fat diet did not alter T3 level in normal hamsters; it increased the low T3 level in myopathic hamsters. Short photoperiod induced a transient increase in T3 level in normal hamsters but not in myopathic hamsters. We conclude that the hypertrophied state of BAT in Syrian hamsters adapted to cold, to high-fat diet, or to short photoperiod is not maintained by elevated norepinephrine secretion and that some other factor(s) must be involved. A selective increase in concentration of BAT mitochondrial uncoupling protein in hamsters may be dependent on raised T3 level in serum and/or production in BAT, since both occur in response to cold acclimation but not in response to high-fat diet or short photoperiod.

Download Full-text

Improved Therapeutic Efficiency against Obesity through Transdermal Drug Delivery Using Microneedle Arrays

Pharmaceutics ◽

10.3390/pharmaceutics13060827 ◽

2021 ◽

Vol 13 (6) ◽

pp. 827

Author(s):

Yixuan Xie ◽

Ruomei Shao ◽

Yali Lin ◽

Chunnan Wang ◽

Ying Tan ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Adrenergic Receptor ◽

Uncoupling Protein ◽

The Body ◽

Control Group ◽

High Fat ◽

Injection Group ◽

Brown Adipose ◽

Injection Dose

In this paper, we prepared patches that were composed of a degradable microneedle (MN) array with a soft backing provided for the skin tissue. We then performed a transdermal delivery of anti-obesity drugs to evaluate the effectiveness of β3 adrenergic receptor CL316243 in obesity treatment in overweight mice induced by a high-fat diet. Eighty male National Institutes of Health (NIH) mice were randomly divided into four obese groups or the control group. The obesity groups were given a high-fat diet for 15–18 weeks to establish an obese model. Afterward, the obese groups were divided into the following four groups: the control group, the unloaded MN group, the CL-316243 MN group, and the injection group. For the injection group, the group of mice was injected subcutaneously with CL316243 (1 mg/(kg·day)) for 15 days. Furthermore, the CL-316243 MN group was given a lower dose (0.1 mg/(kg·day)) for 15 days. After weighing the mice, we used Western blotting to detect the expression of uncoupling protein 1 (UCP1) in the adipose tissue around the mouse viscera. The results stated that the weight of the CL-316243 MN group and the injection group dropped, and the UCP1 protein expression of brown adipose tissue (BAT) significantly increased. The results demonstrated the β3 adrenergic receptor agonist CL316243 could be carried into the body through MN, and the dose applied was considerably smaller than the injection dose. The reason for this may arise from the CL-316243 being delivered by MN arrays to subcutaneous adipose tissue more efficiently, with an even distribution, compared to that of the injection dose. This technique provides a new and feasible way to treat obesity more effectively.

Download Full-text

Eicosapentaenoic Acid Increases Browning Markers in Subcutaneous Adipose Tissue and Primary Adipocytes from Wild Type and UCP-1 Deficient Mice (P15-007-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz037.p15-007-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Shasika Jayarathne ◽

Mandana Pahlavani ◽

Latha Ramalingam ◽

Shane Scoggin ◽

Naima Moustaid-Moussa

Keyword(s):

Adipose Tissue ◽

Eicosapentaenoic Acid ◽

Subcutaneous Adipose Tissue ◽

Uncoupling Protein ◽

Fibroblast Growth Factor 21 ◽

Chow Diet ◽

Mrna Levels ◽

Wild Type ◽

Brown Adipose ◽

Subcutaneous Adipose

Abstract Objectives Brown adipose tissue (BAT) regulates energy balance through thermogenesis, in part via uncoupling protein -1 (UCP-1). White adipose tissue (WAT), namely subcutaneous adipose tissue (SAT) can convert to a beige/brite adipose tissue phenotype (browning) under thermogenic conditions such as cold. We previously reported that eicosapentaenoic acid (EPA) reduced obesity and glucose intolerance, and increased UCP-1 in BAT of B6 mice at ambient temperature (22°C); and these effects were attenuated at thermoneutral environment (28–30°C). We hypothesized that EPA exerts anti-obesity effects on SAT, including increased browning, adipocyte hypotrophy; and these effects require UCP-1. Methods Six-week-old B6 wild type (WT) and UCP-1 knock-out (KO) male mice were maintained at thermoneutral environment and fed high fat diet (HF) with or without 36 g/kg of AlaskOmega EPA-enriched fish oil (800 mg/g) for 14 weeks; and SAT was collected for histological, gene and protein analyses. SAT was also prepared from chow diet-fed WT and KO mice at ambient environment to prepare stroma vascular cells, which were differentiated into adipocytes, treated with 100uM EPA for 48 hours then harvested for mRNA and protein analyses. Results KO mice fed HF diets had the highest body weight (P < 0.05) among all groups. EPA reduced fat cell size in both WT and KO mice fed the EPA diet. mRNA levels of fibroblast growth factor-21 (FGF-21) were higher in SAT of WT mice fed EPA compared to WT mice fed HF (P < 0.05), with no differences between the KO genotype. KO mice fed HF diets had lower levels of UCP-3 in SAT compared to WT mice fed HF (P < 0.05), which was rescued only in the KO mice fed EPA (P < 0.05). UCP-1 protein levels were very low in SAT tissues, and UCP-2 mRNA levels were similar across all groups in SAT. Interestingly, EPA significantly (P < 0.05) increased mRNA expression of UCP-2, UCP-3 and FGF21 in differentiated SAT adipocytes from both WT and KO compared to control. Furthermore, UCP-1 mRNA levels were significantly higher in WT adipocytes treated with EPA, compared to non-treated cells (P < 0.05). Additional mechanistic studies are currently underway to further dissect adipose depot differences in EPA effects in WT vs. KO mice. Conclusions Our data suggest that EPA increases SAT browning, independently of UCP-1. Funding Sources NIH/NCCIH.

Download Full-text

Brown adipose tissue metabolism in ob/ob mice: effects of a high-fat diet and adrenalectomy

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1987.253.2.e149 ◽

1987 ◽

Vol 253 (2) ◽

pp. E149-E157

Author(s):

H. K. Kim ◽

D. R. Romsos

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

High Fat Diet ◽

High Fat ◽

Adipose Tissue Metabolism ◽

High Carbohydrate ◽

Bat Mitochondria ◽

Norepinephrine Turnover ◽

Brown Adipose ◽

Thermogenic Capacity

Adrenalectomy prevents development of obesity in ob/ob mice fed high-carbohydrate stock diets partly by stimulating the low thermogenic capacity of their brown adipose tissue (BAT). Adrenalectomy, however, fails to prevent development of obesity in ob/ob mice fed a high-fat diet. Effects of adrenalectomy on BAT metabolism in ob/ob mice fed a high-fat diet were thus examined. ob/ob mice fed the high-fat diet developed gross obesity despite normal BAT metabolism, as assessed by rates of norepinephrine turnover in BAT, GDP binding to BAT mitochondria, and GDP-inhibitable, chloride-induced mitochondrial swelling. Adrenalectomy failed to arrest the development of obesity or to influence BAT metabolism in ob/ob mice fed the high-fat diet. Development of obesity in ob/ob mice fed a high-fat diet is not associated with low thermogenic capacity of BAT or with adrenal secretions, as it is in ob/ob mice fed high-carbohydrate stock diets.

Download Full-text

GPR120 controls neonatal brown adipose tissue thermogenic induction

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00081.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. E742-E750 ◽

Cited By ~ 2

Author(s):

Tania Quesada-López ◽

Aleix Gavaldà-Navarro ◽

Samantha Morón-Ros ◽

Laura Campderrós ◽

Roser Iglesias ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Uncoupling Protein ◽

Receptor Protein ◽

Brown Adipocyte ◽

Fibroblast Growth Factor 21 ◽

Acid Oxidation ◽

Adaptive Thermogenesis ◽

Brown Adipose ◽

G Protein Coupled

Adaptive induction of thermogenesis in brown adipose tissue (BAT) is essential for the survival of mammals after birth. We show here that G protein-coupled receptor protein 120 (GPR120) expression is dramatically induced after birth in mouse BAT. GPR120 expression in neonatal BAT is the highest among GPR120-expressing tissues in the mouse at any developmental stage tested. The induction of GPR120 in neonatal BAT is caused by postnatal thermal stress rather than by the initiation of suckling. GPR120-null neonates were found to be relatively intolerant to cold: close to one-third did not survive at 21°C, but all such pups survived at 25°C. Heat production in BAT was significantly impaired in GPR120-null pups. Deficiency in GPR120 did not modify brown adipocyte morphology or the anatomical architecture of BAT, as assessed by electron microscopy, but instead impaired the expression of uncoupling protein-1 and the fatty acid oxidation capacity of neonatal BAT. Moreover, GPR120 deficiency impaired fibroblast growth factor 21 (FGF21) gene expression in BAT and reduced plasma FGF21 levels. These results indicate that GPR120 is essential for neonatal adaptive thermogenesis.

Download Full-text

Protective Effects of Individual and Combined Low Dose Beta-Carotene and Metformin Treatments against High-Fat Diet-Induced Responses in Mice

Nutrients ◽

10.3390/nu13103607 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3607

Author(s):

Bojan Stojnić ◽

Alba Serrano ◽

Lana Sušak ◽

Andreu Palou ◽

M. Luisa Bonet ◽

...

Keyword(s):

Adipose Tissue ◽

High Fat Diet ◽

Body Weight Gain ◽

Beta Carotene ◽

Protective Effects ◽

High Fat ◽

Cumulative Energy ◽

Brown Adipose ◽

Obesogenic Diet ◽

Cumulative Energy Intake

Anti-obesity activity has been reported for beta-carotene (BC) supplementation at high doses and metformin (MET). We studied whether BC treatment at a closer to dietary dose and MET treatment at a lower than therapeutic dose are effective in ameliorating unwanted effects of an obesogenic diet and whether their combination is advantageous. Obesity-prone mice were challenged with a high-fat diet (HFD, 45% energy as fat) for 4 weeks while receiving a placebo or being treated orally with BC (3 mg/kg/day), MET (100 mg/kg/day), or their combination (BC+MET); a fifth group received a placebo and was kept on a normal-fat diet (10% energy as fat). HFD-induced increases in body weight gain and inguinal white adipose tissue (WAT) adipocyte size were attenuated maximally or selectively in the BC+MET group, in which a redistribution towards smaller adipocytes was noted. Cumulative energy intake was unaffected, yet results suggested increased systemic energy expenditure and brown adipose tissue activation in the treated groups. Unwanted effects of HFD on glucose control and insulin sensitivity were attenuated in the treated groups, especially BC and BC+MET, in which hepatic lipid content was also decreased. Transcriptional analyses suggested effects on skeletal muscle and WAT metabolism could contribute to better responses to the HFD, especially in the MET and BC+MET groups. The results support the benefits of the BC+MET cotreatment.

Download Full-text