Trends in Endocrinology & Metabolism
ReviewLipoexpediency: de novo lipogenesis as a metabolic signal transmitter
Section snippets
An epidemic with limited novel treatment approaches
Over 40% of Americans have diabetes or prediabetes [1], and as many as a quarter of American adults have the metabolic syndrome which predisposes to diabetes and cardiovascular disease [2]. The health risks of tobacco use have been decreased by public health measures targeted at smoking, but the adverse effects of obesity will probably negate the beneficial effects of declining tobacco use in the United States by 2020 [3]. The metabolic mayhem promoted by a Western lifestyle has been exported
Regulated, tissue-specific flow of carbons to fat
Stored energy is crucial for survival during starvation. Mammals have a limited ability to store energy as carbohydrates but a seemingly unlimited capacity to store calories as fat, which is maladaptive in the industrialized world. In the setting of positive energy balance, carbohydrates can be converted to fatty acids through the process of de novo lipogenesis [14]. Fatty acid biosynthesis is thought to occur to a greater extent in rodents as compared to humans, and is probably a minor
Lipogenesis and PPARα
PPARs are attractive potential molecular mediators of signaling triggered by de novo lipogenesis because this subfamily of nuclear receptors regulates lipid metabolism and inflammation [33]. The three members of this family, PPARα, PPARγ and PPARδ, function as ligand-activated transcription factors that form obligate heterodimers with retinoid X receptors (RXRs) and bind to specific DNA sites known as PPAR response elements (PPREs) located in target gene promoters. Ligand binding induces a
Lipogenic pathways and insulin resistance
Although its clinical hallmark is hyperglycemia, type 2 diabetes is also a disease of impaired lipid metabolism. Fatty acid metabolism is an important regulator of insulin resistance, a central component in the pathogenesis of type 2 diabetes [52]. Insulin, the most potent anabolic hormone, promotes the synthesis and storage of carbohydrates, lipids and proteins and inhibits their degradation [53]. In the setting of insulin resistance, normal circulating concentrations of insulin are
CNS lipogenesis and food intake
Eating less, a more effective approach for weight loss than increasing energy expenditure, is an attractive goal for treating obesity-related diseases. De novo lipogenesis in the brain is involved in regulating food intake but the specific mediators are unknown. FAS inhibitors cause weight loss in mice [61], an effect that could be due to interactions between FAS and the mammalian target of rapamycin complex 1 [62]. Elevated levels of malonyl-CoA, one consequence of FAS inhibition, are
Future directions
It is unrealistic to assume that a culture with ready access to food and social structures that encourage interactions with video monitors will suddenly choose to adopt prudent lifestyle interventions for obesity and its consequences. Because dealing with people in positive energy balance could be inevitable, lipoexpediency, the notion of directing excess calories toward potentially beneficial fats, provides a practical conceptual framework for developing novel treatment paradigms (Figure 3).
De
Acknowledgements
This work was supported by grants DK076729, DK088083, and F32 DK083895 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and Fellowship Awards from the American Heart Association and American Diabetes Association.
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