scholarly journals Glucagon-Receptor Signaling Reverses Hepatic Steatosis Independent of Leptin Receptor Expression

Endocrinology ◽  
2019 ◽  
Vol 161 (1) ◽  
Author(s):  
Shelly R Nason ◽  
Teayoun Kim ◽  
Jessica P Antipenko ◽  
Brian Finan ◽  
Richard DiMarchi ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Leptin Receptor ◽  
Liver Lipid ◽  
Receptor Expression ◽  
Acid Oxidation ◽  
Chow Diet ◽  
Glucagon Receptor ◽  
Leptin Signaling ◽  
Liver Triglycerides ◽  
Lepr Expression

Abstract Glucagon (GCG) is an essential regulator of glucose and lipid metabolism that also promotes weight loss. We have shown that glucagon-receptor (GCGR) signaling increases fatty acid oxidation (FAOx) in primary hepatocytes and reduces liver triglycerides in diet-induced obese (DIO) mice; however, the mechanisms underlying this aspect of GCG biology remains unclear. Investigation of hepatic GCGR targets elucidated a potent and previously unknown induction of leptin receptor (Lepr) expression. Liver leptin signaling is known to increase FAOx and decrease liver triglycerides, similar to glucagon action. Therefore, we hypothesized that glucagon increases hepatic LEPR, which is necessary for glucagon-mediated reversal of hepatic steatosis. Eight-week-old control and liver-specific LEPR-deficient mice (LeprΔliver) were placed on a high-fat diet for 12 weeks and then treated with a selective GCGR agonist (IUB288) for 14 days. Liver triglycerides and gene expression were assessed in liver tissue homogenates. Administration of IUB288 in both lean and DIO mice increased hepatic Lepr isoforms a-e in acute (4 hours) and chronic (72 hours,16 days) (P < 0.05) settings. LeprΔliver mice displayed increased hepatic triglycerides on a chow diet alone (P < 0.05), which persisted in a DIO state (P < 0.001), with no differences in body weight or composition. Surprisingly, chronic administration of IUB288 in DIO control and LeprΔliver mice reduced liver triglycerides regardless of genotype (P < 0.05). Together, these data suggest that GCGR activation induces hepatic Lepr expression and, although hepatic glucagon and leptin signaling have similar liver lipid targets, these appear to be 2 distinct pathways.

1870-P: Glucagon-Receptor Signaling Reverses Hepatic Steatosis Independent of Leptin Receptor Expression

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1870-P
Author(s):  
SHELLY NASON ◽  
TEAYOUN KIM ◽  
JESSICA P. ANTIPENKO ◽  
BRIAN FINAN ◽  
RICHARD DIMARCHI ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Leptin Receptor ◽  
Receptor Expression ◽  
Receptor Signaling ◽  
Glucagon Receptor

scholarly journals Saturated fat-rich diet increases fetal lipids and modulates LPL and leptin receptor expression in rat placentas

2013 ◽  
Vol 217 (3) ◽  
pp. 303-315 ◽  
Author(s):  
M B Mazzucco ◽  
R Higa ◽  
E Capobianco ◽  
M Kurtz ◽  
A Jawerbaum ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Fetal Liver ◽  
Liver Lipid ◽  
Saturated Fat ◽  
Receptor Expression ◽  
Lipid Concentration ◽  
Old Rats ◽  
Liver Lipid Concentration ◽  
Leptin Expression ◽  
Layer Chromatography

Metabolic alterations in obese and overweight mothers impact the placenta and the fetus, leading to anomalies in fetal growth and lipid accretion. The primary aim of the study was to examine the effect of a saturated fat-rich diet (FD) on growth, lipid accretion, and lipases, leptin and leptin receptor (ObR) expression in the placenta and fetal liver. We also aimed to find a role for fetal leptin in the modulation of placental and fetal liver lipase and ObR expression. Six-week-old rats were fed with a standard rat chow (control) or a 25% FD for 7 weeks until mating and during pregnancy. Also, in a group of control rats, fetuses were injected with leptin on days 19, 20, and 21 of pregnancy. On day 21, we assessed lipidemia, insulinemia, and leptinemia in mothers and fetuses. In the placenta and fetal liver, lipid concentration was assessed by thin layer chromatography (TLC) and the gene expression of lipoprotein lipase (LPL), endothelial lipase, insulin receptor (Insr), leptin, and ObR by RT-PCR. The FD induced hypertriglyceridemia and hyperleptinemia (P<0.01) in mothers and fetuses, an increase in maternal (P<0.05) and fetal weight (P<0.01), overaccumulation of lipids in fetal liver (P<0.01), and enhanced leptin expression in the placenta and fetal liver (P<0.05). Placental expression of IR and LPL was increased (P<0.05), and ObR decreased (P<0.05) in the FD group. Fetal administration of leptin induced the placental and fetal liver downregulation of ObR (P<0.05) and upregulation of LPL expression (P<0.05). The FD led to increased fetal lipid levels, which may result from high maternal lipid availability and fetal leptin effects.

scholarly journals Caloric restriction reverses the deficits in leptin receptor protein and leptin signaling capacity associated with diet-induced obesity: role of leptin in the regulation of hypothalamic long-form leptin receptor expression

2004 ◽  
Vol 181 (2) ◽  
pp. 297-306 ◽  
Author(s):  
J Wilsey ◽  
PJ Scarpace
Keyword(s):  
Caloric Restriction ◽  
Leptin Receptor ◽  
Fold Increase ◽  
Receptor Expression ◽  
Male Rats ◽  
Receptor Protein ◽  
Leptin Signaling ◽  
Stat3 Phosphorylation ◽  
Long Form

The objectives of this study were to determine if reduced long-form leptin receptor (ObRb) expression in diet-induced obese (DIO) animals is associated with deficits in maximal leptin signaling and, secondly, to establish the effects of short-term caloric restriction (CR) on ObRb expression and function. Groups of DIO and life-long chow-fed (CHOW) F344xBN male rats, aged 6 months, were given an i.c.v. injection containing 2 micro g leptin or artificial cerebrospinal fluid (ACSF) vehicle. Leptin induced a >6-fold increase in STAT3 phosphorylation in CHOW rats, but less than 2-fold increase in DIO. Reduced maximal leptin-stimulated STAT3 phosphorylation in DIO rats was coupled with a decline in both ObRb expression and protein. At this point, subgroups of DIO and CHOW animals underwent CR for 30 days and were then tested for acute leptin responsiveness. CR resulted in a 45 and 85% increase respectively in leptin-stimulated STAT3 phosphorylation in CHOW and DIO animals. Similarly, CR increased ObRb expression and protein in both CHOW and DIO animals. To explore the role of leptin in regulating ObRb expression, we reversibly overexpressed leptin in the hypothalamus and found that ObRb mRNA inversely follows central leptin expression. By enhancing both ObRb expression and signaling capacity, CR may enhance leptin responsiveness in leptin-resistant DIO animals.

scholarly journals Altered Brain Leptin and Leptin Receptor Expression in the 5XFAD Mouse Model of Alzheimer’s Disease

2020 ◽  
Vol 13 (11) ◽  
pp. 401
Author(s):  
Anishchal A. Pratap ◽  
R. M. Damian Holsinger
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Leptin Receptor ◽  
Neurodegenerative Disorder ◽  
Receptor Expression ◽  
Immunofluorescent Staining ◽  
5Xfad Mouse ◽  
5Xfad Mice ◽  
Lepr Expression

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Interestingly, individuals with metabolic syndromes share some pathologies with those diagnosed with AD including neuroinflammation, insulin resistance and cognitive deficits. Leptin, an adipocyte-derived hormone, regulates metabolism, energy expenditure and satiety via its receptor, LepR. To investigate the possible involvement of leptin in AD, we examined the distribution of leptin and LepR in the brains of the 5XFAD mouse model of AD, utilizing immunofluorescent staining in young (10–12-weeks; n = 6) and old (48–52-weeks; n = 6) transgenic (Tg) mice, together with age-matched wild-type (WT) controls for both age groups (young-WT, n = 6; old-WT, n = 6). We also used double immunofluorescent staining to examine the distribution of leptin and leptin receptor expression in astrocytes. In young 5XFAD, young-WT and old-WT mice, we observed neuronal and endothelial expression of leptin and LepR throughout the brain. However, neuronal leptin and LepR expression in the old 5XFAD brain was significantly diminished. Reduced neuronal leptin and LepR expression was accompanied by plaque loading and neuroinflammation in the AD brain. A marked increase in astrocytic leptin and LepR was also observed in old 5XFAD mice compared to younger 5XFAD mice. We postulate that astrocytes may utilize LepR signalling to mediate and drive their metabolically active state when degrading amyloid in the AD brain. Overall, these findings provide evidence of impaired leptin and LepR signalling in the AD brain, supporting clinical and epidemiological studies performed in AD patients.

scholarly journals Dietary Oxysterol, 7-Ketocholesterol Accelerates Hepatic Lipid Accumulation and Macrophage Infiltration in Obese Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiuyang Chang ◽  
Masahiro Koseki ◽  
Ayami Saga ◽  
Kotaro Kanno ◽  
Tomoaki Higo ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Lipid Extraction ◽  
Acid Oxidation ◽  
Chow Diet ◽  
Obese Mice ◽  
Mice Model ◽  
Alcoholic Fatty Liver ◽  
Hepatic Lipid Accumulation

Non-alcoholic fatty liver disease is strongly associated with obese and type 2 diabetes. It has been reported that an oxidized cholesterol, 7-ketocholesterol (7KC), might cause inflammatory response in macrophages and plasma 7KC concentration were higher in patients with cardiovascular diseases or diabetes. Therefore, we have decided to test whether small amount of 7KC in diet might induce hepatic steatosis and inflammation in two types of obese models. We found that addition of 0.01% 7KC either in chow diet (CD, regular chow diet with 1% cholesterol) or western type diet (WD, high fat diet with 1% cholesterol) accelerated hepatic neutral lipid accumulation by Oil Red O staining. Importantly, by lipid extraction analysis, it has been recognized that triglyceride rather than cholesterol species was significantly accumulated in CD+7KC compared to CD as well as in WD+7KC compared to WD. Immunostaining revealed that macrophages infiltration was increased in CD+7KC compared to CD, and also in WD+7KC compared to WD. These phenotypes were accompanied by inducing inflammatory response and downregulating fatty acid oxidation. Furthermore, RNA sequence analysis demonstrated that 7KC reduced expression of genes which related to autophagy process. Levels of LC3-II protein were decreased in WD+7KC compared to WD. Similarly, we have confirmed the effect of 7KC on acceleration of steatohepatitis in db/db mice model. Collectively, our study has demonstrated that small amount of dietary 7KC contributed to accelerate hepatic steatosis and inflammation in obese mice models.

scholarly journals Arcuate Nucleus-Specific Leptin Receptor Gene Therapy Attenuates the Obesity Phenotype of Koletsky (fak/fak) Rats

Endocrinology ◽  
2003 ◽  
Vol 144 (5) ◽  
pp. 2016-2024 ◽  
Author(s):  
Gregory J. Morton ◽  
Kevin D. Niswender ◽  
Christopher J. Rhodes ◽  
Martin G. Myers ◽  
James E. Blevins ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Body Weight ◽  
Food Intake ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Receptor Expression ◽  
Wild Type ◽  
Leptin Signaling ◽  
Adenoviral Gene Therapy

Leptin signaling in the hypothalamic arcuate nucleus (ARC) is hypothesized to play an important role in energy homeostasis. To investigate whether leptin signaling limited to this brain area is sufficient to reduce food intake and body weight, we used adenoviral gene therapy to express the signaling isoform of the leptin receptor, leprb, in the ARC of leptin receptor-deficient Koletsky (fak/fak) rats. Successful expression of adenovirus containing leprb (Ad-leprb) selectively in the ARC was documented by in situ hybridization. Using real-time PCR, we further demonstrated that bilateral microinjection of Ad-leprb into the ARC restored low hypothalamic levels of leprb mRNA to values approximating those of wild-type (Fak/Fak) controls. Restored leptin receptor expression in the ARC reduced both mean daily food intake (by 13%) and body weight gain (by 33%) and increased hypothalamic proopiomelanocortin mRNA by 65% while decreasing neuropeptide Y mRNA levels by 30%, relative to fak/fak rats injected with a control adenovirus (Ad-lacZ) (P &lt; 0.05 for each comparison). In contrast, Ad-leprb delivery to either the lateral hypothalamic area of fak/fak rats or to the ARC of wild-type Fak/Fak rats had no effect on any of these parameters. These findings collectively support the hypothesis that leptin receptor signaling in the ARC is sufficient to mediate major effects of leptin on long-term energy homeostasis. Adenoviral gene therapy is thus a viable strategy with which to study the physiological importance of specific molecules acting in discrete brain areas.

scholarly journals PEGylated Curcumin Derivative Attenuates Hepatic Steatosis via CREB/PPAR-γ/CD36 Pathway

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Yu Liu ◽  
Fei Cheng ◽  
Yuxuan Luo ◽  
Zhu Zhan ◽  
Peng Hu ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Liver Lipid ◽  
Serum Triglyceride ◽  
The Body ◽  
Chow Diet ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Curcumin Derivative

Curcumin has the potential to cure dyslipidemia and nonalcoholic fatty liver disease (NAFLD). However, its therapeutic effects are curbed by poor bioavailability. Our previous work has shown that modification of curcumin with polyethylene glycol (PEG) improves blood concentration and tissue distribution. This study sought to investigate the role of a novel PEGylated curcumin derivative (Curc-mPEG454) in regulating hepatic lipid metabolism and to elucidate the underlying molecular mechanism in a high-fat-diet- (HFD-) fed C57BL/6J mouse model. Mice were fed either a control chow diet (D12450B), an HFD (D12492) as the NAFLD model, or an HFD with Curc-mPEG454 administered by intraperitoneal injection at 50 mg/kg or 100 mg/kg for 16 weeks. We found that Curc-mPEG454 significantly lowered the body weight and serum triglyceride (TG) levels and reduced liver lipid accumulation in HFD-induced NAFLD mice. It was also shown that Curc-mPEG454 suppressed the HFD-induced upregulated expression of CD36 and hepatic peroxisome proliferator activated receptor-γ (PPAR-γ), a positive regulator of CD36. Moreover, Curc-mPEG454 dramatically activated cAMP response element-binding (CREB) protein, which negatively controls hepatic PPAR-γ expression. These findings suggest that Curc-mPEG454 reverses HFD-induced hepatic steatosis via the activation of CREB inhibition of the hepatic PPAR-γ/CD36 pathway, which may be an effective therapeutic for high-fat-diet-induced NAFLD.

scholarly journals Aerobic capacity and hepatic mitochondrial lipid oxidation alters susceptibility for chronic high-fat diet-induced hepatic steatosis

2016 ◽  
Vol 311 (4) ◽  
pp. E749-E760 ◽  
Author(s):  
E. Matthew Morris ◽  
Grace M. E. Meers ◽  
Lauren G. Koch ◽  
Steven L. Britton ◽  
Justin A. Fletcher ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Aerobic Capacity ◽  
High Capacity ◽  
Tca Cycle ◽  
Oxidative Capacity ◽  
Acid Oxidation ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
Mitochondrial Oxidative Capacity ◽  
Liver Triglycerides

Rats selectively bred for high capacity running (HCR) or low capacity running (LCR) display divergence for intrinsic aerobic capacity and hepatic mitochondrial oxidative capacity, both factors associated with susceptibility for nonalcoholic fatty liver disease. Here, we tested if HCR and LCR rats display differences in susceptibility for hepatic steatosis after 16 wk of high-fat diets (HFD) with either 45% or 60% of kcals from fat. HCR rats were protected against HFD-induced hepatic steatosis, whereas only the 60% HFD induced steatosis in LCR rats, as marked by a doubling of liver triglycerides. Hepatic complete fatty acid oxidation (FAO) and mitochondrial respiratory capacity were all lower in LCR compared with HCR rats. LCR rats also displayed lower hepatic complete and incomplete FAO in the presence of etomoxir, suggesting a reduced role for noncarnitine palmitoyltransferase-1-mediated lipid catabolism in LCR versus HCR rats. Hepatic complete FAO and mitochondrial respiration were largely unaffected by either chronic HFD; however, 60% HFD feeding markedly reduced 2-pyruvate oxidation, a marker of tricarboxylic acid (TCA) cycle flux, and mitochondrial complete FAO only in LCR rats. LCR rats displayed lower levels of hepatic long-chain acylcarnitines than HCR rats but maintained similar levels of hepatic acetyl-carnitine levels, further supporting lower rates of β-oxidation, and TCA cycle flux in LCR than HCR rats. Finally, only LCR rats displayed early reductions in TCA cycle genes after the acute initiation of a HFD. In conclusion, intrinsically high aerobic capacity confers protection against HFD-induced hepatic steatosis through elevated hepatic mitochondrial oxidative capacity.

TNF and IL-18 cytokines may regulate liver fat storage under homeostasis conditions

2016 ◽  
Vol 41 (12) ◽  
pp. 1295-1302 ◽  
Author(s):  
Jaqueline Pereira Lana ◽  
Laís Bhering Martins ◽  
Marina Chaves de Oliveira ◽  
Zélia Menezes-Garcia ◽  
Letícia Tamie Pavia Yamada ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Liver Lipid ◽  
Liver Fat ◽  
Chow Diet ◽  
Tnf Receptor ◽  
Fat Storage ◽  
Lipid Dynamics ◽  
Liver Triglycerides ◽  
Total Fat

The inflammation induced by obesogenic diets is associated with deposition of fat in the liver. On the other hand, anti-inflammatory and immunosuppressive therapies may impact in body fat storage and in liver lipid dynamics. It is important to study specific inflammatory mediators in this context, since their role on hepatic damage is not fully clarified. This study aimed to evaluate the role of interleukin (IL)-18 and tumor necrosis factor (TNF) receptor in liver dysfunction induced by diet. Male C57BL/6 wild-type (WT), IL-18, and TNF receptor 1 knockout mice (IL-18−/−and TNFR1−/−) were divided according to the experimental diets: chow diet or a high-refined carbohydrate-containing diet. Alanine aminotransferase was quantified by colorimetric analysis. Total fat content in the liver was determined by Folch methods. Levels of TNF, IL-6, IL-4, and IL-13 in liver samples were measured by ELISA assay. IL-18 and TNFR knockout mice fed with chow diet showed higher liver triglycerides deposition than WT mice fed with the same diet (WT: 131.9 ± 24.5; IL-18−/−: 239.4 ± 38.12*; TNF−/−: 179.6 ± 50.45*; *P < 0.01). Furthermore, these animals also showed a worse liver histopathological score and lower levels of TNF, IL-6, IL-4, and IL-13 in the liver. Interestingly, treatment with a high-carbohydrate diet did not exacerbate liver damage in IL-18−/−and TNFR1−/−mice. Our data suggest that IL-18 and TNF may be involved on hepatic homeostasis mainly in a context of a healthy diet.

Abstract 5525: Leptin Receptor Signaling Pathways are protective Against Atherosclerosis in a Mouse Model of Obesity and Hyperlipidemia

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Wei Luo ◽  
Yuechun Shen ◽  
Kevin Wickenheiser ◽  
Miina Öhman ◽  
Martin Myers ◽  
...  
Keyword(s):  
Mouse Model ◽  
Signaling Pathways ◽  
Hepatic Steatosis ◽  
Leptin Receptor ◽  
Heart Association ◽  
Receptor Expression ◽  
Metabolic Effects ◽  
Receptor Signaling ◽  
Vascular Effects ◽  
Adipose Inflammation

Leptin is an adipocyte-derived hormone that has been shown to exert both beneficial metabolic effects and potentially adverse vascular effects in preclinical studies. To determine the effects of leptin receptor signaling pathways on atherosclerosis in the setting of obesity and hyperlipidemia, mice were generated with deficiency of apolipoprotein E ( ApoE −/− ) and either wild-type leptin receptor expression ( Lepr +/+ ,ApoE −/− ), mutant leptin receptor expression defective in all leptin receptor signaling pathways ( Lepr db/db ,ApoE −/− ), or mutant leptin receptor with selective deficiency of leptin receptor-STAT3 signaling ( Lepr s/s ,ApoE −/− ). At 27 weeks of age, which included 7 weeks on western chow, Lepr db/db ,ApoE −/− developed increased weight (61.9 ±3.5 vs 28±2.5, p<0.001), increased leptin (127.8±34 vs 24±12.5, p<0.003), increased NEFAC (2.4±0.75 vs 0.65±0.11, p<0.05) and more atherosclerosis (13.9±1.7 vs 4.3±0.9, p=0.001) than Lepr +/+ ,ApoE −/− mice. In contrast, despite similar obesity and hyperlipidemia to Lepr db/db ,ApoE −/− mice, the atherosclerosis in Lepr s/s ,ApoE −/− was less than Lepr db/db ,ApoE −/− mice (7.3±1 vs 13.9±1.7, p=0.003) and not significantly greater than Lepr +/+ ,ApoE −/− mice (7.3±1 vs 4.3±0.9, p=0.06 ). Hepatic steatosis and adipose inflammation were also reduced in Lepr s/s ,ApoE −/− mice compared to Lepr db/db ,ApoE −/− mice. In a mouse model of obesity and hyperlipidemia, leptin receptor signaling confers protection against hepatic steatosis, fat inflammation, and atherosclerosis. These effects are independent of leptin effects on energy balance. This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).

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