Fatty acid metabolism as a target for obesity treatment

@article{Ronnett2005FattyAM,
  title={Fatty acid metabolism as a target for obesity treatment},
  author={Gabriele V. Ronnett and Eun-Kyoung Kim and Leslie E. Landree and Yajun Tu},
  journal={Physiology \& Behavior},
  year={2005},
  volume={85},
  pages={25-35}
}

C75, a Fatty Acid Synthase (FAS) Inhibitor

What is known about hypothalamic fatty acid metabolism and the regulation of feeding is recapitulate, with particular interest in a specific FAS inhibitor, C75, which has been recently patented as a potential drug for adipose treatment.

Increasing Fatty Acid Oxidation Remodels the Hypothalamic Neurometabolome to Mitigate Stress and Inflammation

It is proposed that enhancing FAOx in hypothalamic neurons exposed to excess lipids promotes metabolic remodeling that reduces local inflammatory and cell stress responses and restore mitochondrial function such that increased FAOx can produce hypothalamic neuronal ATP and lead to decreased food intake and body weight to improve systemic metabolism.

The Effects of C75, an Inhibitor of Fatty Acid Synthase, on Sleep and Metabolism in Mice

The findings suggest that sleep and metabolic effects of C75 in mice are independent of the ghrelin system and may be due to its aversive actions in mice.

[Role of fatty acids in the nervous control of energy balance].

FA overload might impair neural control of energy homeostasis through enhanced ceramide synthesis and may contribute to obesity and/or type 2 diabetes pathogenesis in predisposed subjects.

Fatty Acid Synthase Inhibitors Modulate Energy Balance via Mammalian Target of Rapamycin Complex 1 Signaling in the Central Nervous System

Findings collectively indicate an important interaction between the FAS and mTORC1 pathways in the central nervous system for regulating energy balance, possibly via modulation of neuronal glucose utilization.

The Role of Hypothalamic Malonyl-CoA in Energy Homeostasis*

A role for malonyl-CoA as an intermediary in the control of energy homeostasis is supported by physiologic, pharmacologic, and genetic evidence implicated in this energy-sensing system.

Effects of β‐aminoisobutyric acid on leptin production and lipid homeostasis: mechanisms and possible relevance for the prevention of obesity

The circumstances that led to the discovery of BAIBA, and recent data from other investigators suggesting that increasing leptin levels and/or responsiveness may be indeed an attractive pharmacological strategy in order to prevent (and/or treat) obesity, are recalled.

Brain lipid sensing and the neural control of energy balance

The Effects of New Selective PPARα Agonist CP775146 on Systematic Lipid Metabolism in Obese Mice and Its Potential Mechanism

CP775146 efficiently alleviates obesity-induced liver damage, prevents lipid accumulation by activating the liver fatty acid β-oxidation pathway, and regulates the expression of genes that control brown fat-like pathway in eWAT.
...

References

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C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity

C75 acts both centrally to reduce food intake and peripherally to increase fatty acid oxidation, leading to rapid and profound weight loss, loss of adipose mass, and resolution of fatty liver, in mice and cellular models.

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

Modulation of FAS activity in the hypothalamus can alter energy perception via AMPK, which functions as a physiological energy sensor in the amygdala, which regulates feeding behavior and mediates the anorexic effects of C75.

C75, a Fatty Acid Synthase Inhibitor, Modulates AMP-activated Protein Kinase to Alter Neuronal Energy Metabolism*

It is demonstrated that in primary cortical neurons, C75 inhibits FAS activity and stimulates carnitine palmitoyltransferase-1 (CPT-1), consistent with its effects in peripheral tissues, and that C75 modulates the levels of energy intermediates, thus, affecting the energy sensor AMPK.

C75 alters central and peripheral gene expression to reduce food intake and increase energy expenditure.

Gene expression changes in peripheral tissues indicated that C75 increased energy expenditure by the induction of genes involved in fatty acid oxidation, and patterns of the changes in central and peripheral gene expression that occur with C75 treatment provide mechanisms to explain the reduced food intake and increase energy expenditure observed with C 75.

Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides

In both lean and obese mice, C75 markedly increased expression of melaninconcentrating hormone and its receptor in the hypothalamus and had no effect on the expression of POMC and CART mRNAs.

Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production

Results indicated that changes in the rate of lipid oxidation in selective hypothalamic neurons signaled nutrient availability to the hypothalamus, which in turn modulated the exogenous and endogenous inputs of nutrients into the circulation.

Influence of fatty acid oxidation in lateral hypothalamus on food intake and body composition.

The results of this experiment indicate that the level of fatty acid oxidation in the VLH is unlikely to independently elicit changes in food intake or peripheral metabolism.

Differential effects of a centrally acting fatty acid synthase inhibitor in lean and obese mice

In contrast to the short-term effects of C75 on “fasting-induced” changes of hypothalamic orexigenic and anorexigenic neuropeptide mRNAs, repeated treatment with C75 either had the inverse or no effect as tolerance developed, and Pair-fed controls lost 24–50% less body weight than C75-treated mice, indicating that, in addition to suppressing food intake, C75 may increase energy expenditure.
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