Lipoexpediency: de novo lipogenesis as a metabolic signal transmitter

doi:10.1016/j.tem.2010.09.002

Trends in Endocrinology & Metabolism

Volume 22, Issue 1, January 2011, Pages 1-8

https://doi.org/10.1016/j.tem.2010.09.002 Get rights and content

De novo lipogenesis, the production of fats from simple precursors, is often dismissed as irrelevant to the pathobiology of obesity caused by positive energy balance due to typical high fat diets. However, emerging data implicate de novo lipogenesis in the generation of metabolic signals that alter disease risk. Exploiting this signaling pathway represents lipoexpediency. Lipoexpediency is the concept of directing fats toward benefit even in the setting of lipid overload, and represents a strategy to complement efforts aimed at improving energy balance. Optimizing lipid signals initiated by key lipogenic enzymes such as fatty acid synthase might limit morbidity in people who are unlikely to abandon the lifestyle of the sedentary gourmand.

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).

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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Trends in Endocrinology & Metabolism

ReviewLipoexpediency: de novo lipogenesis as a metabolic signal transmitter

Section snippets

An epidemic with limited novel treatment approaches

Regulated, tissue-specific flow of carbons to fat

Lipogenesis and PPARα

Lipogenic pathways and insulin resistance

CNS lipogenesis and food intake

Future directions

Acknowledgements

Cell Metab.

Prog. Lipid Res.

J. Lipid Res.

Am. J. Clin. Nutr.

J. Biol. Chem.

Cell

Cell Metab.

Cell Metab.

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Trends Endocrinol. Metab.

Biochim. Biophys. Acta

Cell

Cell Metab.

Cell Metab.

Cell

Cell

Cell Metab.

Full accounting of diabetes and pre-diabetes in the U.S. population in 1988-1994 and 2005-2006

Diabetes Care

Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey

J. Am. Med. Assoc.

Forecasting the effects of obesity and smoking on U.S. life expectancy

N. Engl. J. Med.

Prevalence of diabetes among men and women in China

N. Engl. J. Med.

Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications

Hepatology

Diabetes and apoptosis: lipotoxicity

Apoptosis

Identification and characterization of metabolically benign obesity in humans

Arch. Intern. Med.

Obesity-associated improvements in metabolic profile through expansion of adipose tissue

J. Clin. Invest.

DGAT1-dependent triacylglycerol storage by macrophages protects mice from diet-induced insulin resistance and inflammation

J. Clin. Invest.

Skeletal muscle lipid content and insulin resistance: evidence for a paradox in endurance-trained athletes

J. Clin. Endocrinol. Metab.

Lipid signalling in disease

Nat. Rev. Mol. Cell Biol.

Anti-inflammatory and proresolving lipid mediators

Annu. Rev. Pathol.

Review
Lipoexpediency: de novo lipogenesis as a metabolic signal transmitter