scholarly journals C75, a Fatty Acid Synthase Inhibitor, Reduces Food Intake via Hypothalamic AMP-activated Protein Kinase

2004 ◽  
Vol 279 (19) ◽  
pp. 19970-19976 ◽  
Author(s):  
Eun-Kyoung Kim ◽  
Ian Miller ◽  
Susan Aja ◽  
Leslie E. Landree ◽  
Michael Pinn ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Fatty Acid ◽  
Energy Balance ◽  
Protein Kinase ◽  
Food Intake ◽  
Fatty Acid Synthase ◽  
Α Subunit ◽  
Compound C ◽  
Amp Activated Protein Kinase

Energy homeostasis and feeding are regulated by the central nervous system. C75, a fatty acid synthase (FAS) inhibitor, causes weight loss and anorexia, implying a novel central nervous system pathway(s) for sensing energy balance. AMP-activated protein kinase (AMPK), a sensor of peripheral energy balance, is phosphorylated and activated when energy sources are low. Here, we identify a role for hypothalamic AMPK in the regulation of feeding behavior and in mediating the anorexic effects of C75. 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), an activator of AMPK, increased food intake, whereas compound C, an inhibitor of AMPK, decreased food intake. C75 rapidly reduced the level of the phosphorylated AMPK α subunit (pAMPKα) in the hypothalamus, even in fasted mice that had elevated hypothalamic pAMPKα levels. Furthermore, AICAR reversed both the C75-induced anorexia and the decrease in hypothalamic pAMPKα levels. C75 elevated hypothalamic neuronal ATP levels, which may contribute to the mechanism by which C75 decreased AMPK activity. C75 reduced the levels of pAMPKα and phosphorylated cAMP response element-binding protein (pCREB) in the arcuate nucleus neurons of the hypothalamus, suggesting a mechanism for the reduction in NPY expression seen with C75 treatment. These data indicate that modulation of FAS activity in the hypothalamus can alter energy perception via AMPK, which functions as a physiological energy sensor in the hypothalamus.

scholarly journals Dorsal Hindbrain 5′-Adenosine Monophosphate-Activated Protein Kinase as an Intracellular Mediator of Energy Balance

Endocrinology ◽  
2008 ◽  
Vol 150 (5) ◽  
pp. 2175-2182 ◽  
Author(s):  
Matthew R. Hayes ◽  
Karolina P. Skibicka ◽  
Kendra K. Bence ◽  
Harvey J. Grill
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Energy Balance ◽  
Protein Kinase ◽  
Food Intake ◽  
Nucleus Tractus Solitarius ◽  
Balance Control ◽  
Whole Body ◽  
Compound C ◽  
Ampk Activity

The fuel-sensing enzyme AMP-activated protein kinase (AMPK) has been implicated in central nervous system control of energy balance. Hypothalamic AMPK activity is increased by food deprivation, and this elevation is inhibited by refeeding or by leptin treatment. The contribution of extrahypothalamic AMPK activity in energy balance control has not been addressed. Here, we investigate the effects of physiological state on the AMPK activity in hindbrain nucleus tractus solitarius (NTS) neurons because treatments that reduce energy availability in these neurons trigger behavioral, endocrine, and autonomic responses to restore energy balance. Food-deprived rats showed significantly increased AMPK activity in both NTS- and hypothalamus-enriched lysates compared with those that were ad libitum fed. Pharmacological inhibition of AMPK activity in medial NTS neurons, by intraparenchymal injection of compound C, suppressed food intake and body weight gain compared with vehicle. Fourth ventricle (4th icv) compound C delivery increased heart rate and spontaneous activity in free-moving rats. Suppression of AMPK activity has been implicated in leptin’s anorectic action in the hypothalamus. Given the role of leptin signaling in food intake inhibition within the medial NTS, we also examined whether stimulation of hindbrain AMPK by 4th icv administration of 5-aminoimidazole-4-carboxamide-riboside (AICAR), an AMP-mimicking promoter of AMPK activity, could attenuate the inhibition of food intake by 4th icv leptin. The intake-suppressive effects of leptin (at 2 and 4 h) were completely reversed by AICAR. We conclude that 1) hindbrain AMPK activity contributes to energy balance control through regulation of food intake and energy expenditure, 2) leptin’s intake-reducing effects in the NTS are meditated by AMPK, and 3) central nervous system AMPK controls whole-body homeostasis at anatomically distributed sites across the neuraxis.

scholarly journals Catalpol Attenuates Hepatic Steatosis by Regulating Lipid Metabolism via AMP-Activated Protein Kinase Activation

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Xiang Tian ◽  
Qin Ru ◽  
Qi Xiong ◽  
Ruojian Wen ◽  
Yong Chen
Keyword(s):  
Fatty Acid ◽  
Protein Kinase ◽  
Hepatic Steatosis ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Fatty Acid Synthase ◽  
Target Genes ◽  
Dependent Manner ◽  
Compound C ◽  
Amp Activated Protein Kinase

The increased prevalence of nonalcoholic fatty liver disease (NAFLD), which develops from hepatic steatosis, represents a public health challenge. Catalpol, a natural component extracted from the roots of Radix Rehmanniae, has several pharmacological activities. The present study is aimed at examining whether catalpol prevents hepatic steatosis in cell and animal experiments and elucidating the possible mechanisms. HepG2 cells were treated with 300 μM palmitate (PA) and/or catalpol for 24 h in vitro, and male C57BL/6J mice fed a high-fat diet (HFD) were administered catalpol for 18 weeks in vivo. The results revealed that catalpol significantly decreased lipid accumulation in PA-treated HepG2 cells. Moreover, catalpol drastically reduced body weight and lipid accumulation in the liver, whereas it ameliorated hepatocyte steatosis in HFD-fed mice. Notably, catalpol remarkably promoted the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. Subsequently, catalpol repressed the expressions of lipogenesis-associated genes such as sterol regulatory element-binding protein 1c and fatty acid synthase but promoted the expressions of genes associated with fatty acid β-oxidation such as peroxisome proliferator-activated receptor α together with its target genes carnitine palmitoyltransferase 1 and acyl-CoA oxidase 1 (ACOX1). However, the preincubation of the HepG2 cells with compound C (10 μM), an AMPK inhibitor, prevented catalpol-mediated beneficial effects. These findings suggest that catalpol ameliorates hepatic steatosis by suppressing lipogenesis and enhancing fatty acid β-oxidation in an AMPK-dependent manner. Therefore, catalpol has potential as a novel agent in the treatment of NAFLD.

scholarly journals Involvement of AMP-activated protein kinase in thrombin-stimulated interleukin 6 synthesis in osteoblasts

2012 ◽  
Vol 49 (1) ◽  
pp. 47-55 ◽  
Author(s):  
H Tokuda ◽  
K Kato ◽  
H Natsume ◽  
A Kondo ◽  
G Kuroyanagi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Interleukin 6 ◽  
P38 Map Kinase ◽  
Thrombin Time ◽  
Rt Pcr ◽  
Α Subunit ◽  
Compound C ◽  
Kinase C ◽  
Amp Activated Protein Kinase

We previously demonstrated that thrombin stimulates synthesis of interleukin 6 (IL6), a potent bone resorptive agent, in part via p44/p42 MAP kinase and p38 MAP kinase but not through stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) among the MAP kinase superfamily in osteoblast-like MC3T3-E1 cells. In this study, we investigated the involvement of AMP-activated protein kinase (AMPK), a regulator of energy metabolism, in thrombin-stimulated IL6 synthesis in MC3T3-E1 cells. The phosphorylation of p44/p42 MAP kinase, p38 MAP kinase, SAPK/JNK, or AMPK was determined by western blot analysis. The release of IL6 was determined by the measurement of IL6 concentration in the conditioned medium using an ELISA kit. The expression ofIL6mRNA was determined by RT-PCR. Thrombin time dependently induced the phosphorylation of AMPK α-subunit (Thr-172). Compound C, an inhibitor of AMPK, dose-dependently suppressed the thrombin-stimulated IL6 release in the range between 0.3 and 10 μM. Compound C reduced thrombin-induced acetyl-CoA carboxylase phosphorylation. TheIL6mRNA expression induced by thrombin was markedly reduced by compound C. Downregulation of AMPK by siRNA suppressed the thrombin-stimulated IL6 release. The thrombin-induced phosphorylation of p44/p42 MAP kinase and p38 MAP kinase was inhibited by compound C, which failed to affect SAPK/JNK phosphorylation. These results strongly suggest that AMPK regulates thrombin-stimulated IL6 synthesis via p44/p42 MAP kinase and p38 MAP kinase in osteoblasts.

scholarly journals AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage–Th17 Axis

2016 ◽  
Vol 197 (3) ◽  
pp. 747-760 ◽  
Author(s):  
Ashutosh K. Mangalam ◽  
Ramandeep Rattan ◽  
Hamid Suhail ◽  
Jaspreet Singh ◽  
Md Nasrul Hoda ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Protein Kinase ◽  
Central Nervous System Disease ◽  
Nervous System Disease ◽  
System Disease ◽  
Amp Activated Protein Kinase ◽  
M1 Type

scholarly journals Circadian Feeding Drive of Metabolic Activity in Adipose Tissue and not Hyperphagia Triggers Overweight in Mice: Is There a Role of the Pentose-Phosphate Pathway?

Endocrinology ◽  
2012 ◽  
Vol 153 (2) ◽  
pp. 690-699 ◽  
Author(s):  
Paula Stucchi ◽  
Marta Gil-Ortega ◽  
Beatriz Merino ◽  
Rocío Guzmán-Ruiz ◽  
Victoria Cano ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Food Intake ◽  
Pentose Phosphate Pathway ◽  
Fatty Acid Synthase ◽  
Pentose Phosphate ◽  
Plasma Parameters ◽  
Dependent Protein Kinase ◽  
Dependent Protein

High-fat (HF) diets trigger an increase in adipose tissue and body weight (BW) and disordered eating behavior. Our study deals with the hypothesis that circadian distribution of energy intake is more relevant for BW dynamics than diet composition. Four-week-old mice were exposed for 8 wk to a HF diet and compared with animals receiving control chow. HF mice progressively increased BW, decreased the amount of nocturnal (1800–0900 h) calories (energy or food intake) (30%) and increased diurnal (0900–1800 h) caloric intake (energy or food intake), although total daily intake was identical between groups. Animals were killed at 3-h intervals and plasma insulin, leptin, corticosterone, glucose, and fatty acid levels quantified. Adipose tissue was weighed, and enzymatic activities integral to the pentose phosphate pathway (PPP) assayed in lumbar adipose tissue. Phosphorylated AMP-dependent protein kinase and fatty acid synthase were quantified by Western blotting. In HF mice, there was a shift in the circadian oscillations of plasma parameters together with an inhibition of PPP activity and a decrease in phosphorylated AMP-dependent protein kinase and fatty acid synthase. In a second experiment, HF mice were forced to adhere to a circadian pattern of food intake similar to that in control animals. In this case, BW, adipose tissue, morning plasma parameters and PPP activity appeared to be normal. These data indicate that disordered feeding behavior can trigger BW gain independently of food composition and daily energy intake. Because PPP is the main source of reduced nicotinamide adenine dinucleotide phosphate, we suggest that PPP inhibition might be an early marker of adipose dysfunction in diet-induced obesity.

scholarly journals Fatty Acid Synthase Inhibition Activates AMP-Activated Protein Kinase in SKOV3 Human Ovarian Cancer Cells

2007 ◽  
Vol 67 (7) ◽  
pp. 2964-2971 ◽  
Author(s):  
Weibo Zhou ◽  
Wan Fang Han ◽  
Leslie E. Landree ◽  
Jagan N. Thupari ◽  
Michael L. Pinn ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Fatty Acid Synthase ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Amp Activated Protein Kinase
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