Studies in recent years have identified adipose tissue as a critical site for whole body metabolic regulation. Growing evidence supports the concept that peptides and hormones produced within adipose tissue constitute an important component of the endocrine effects of this site on systemic carbohydrate and lipid homeostasis. As the major storage site for lipids, adipose tissue has also been studied intensively in regards to its role in metabolic regulation through lipid signaling. While equally critical as peptide hormones, this area has been more challenging to reduce into molecular entities and pathways. There are two prevailing views about the role of adipose tissue lipid metabolism in metabolic syndrome. First, storage of lipids in adipose tissue has been suggested to protect other organs from exposure to excessive lipids and thereby reducing the risk of lipotoxicity. Second, fatty acids derived from adipose tissue, particularly under obese conditions, could disrupt the function of peripheral tissues, resulting in muscle insulin resistance or hepatic steatosis. In these models, the principal consideration has often been the total amount of lipid exposure at target tissues. However, serum lipids are very complex entities composed of structures with varying chain length and saturation. The concentration and composition of fatty acids also vary significantly under different physiological and pathological conditions. Although it is unlikely that evaluation of total fatty acid levels alone is sufficiently informative, there has been little progress in addressing how different compositions of fatty acids in tissues or circulation affect the metabolic output, as this has been experimentally challenging. Another intractable question concerns how lipid storing and/or disposing tissues respond to dietary fatty acid intake and adjust their composition and hormonal output to modulate systemic metabolism.
In this report, we took advantage of high resolution, quantitative lipidomic analysis combined with functional experimentation to approach these questions. We also utilized the striking impact of lipid chaperones on these paradigms in vivo to identify lipid pathways that contribute to systemic metabolic homeostasis. These approaches yielded several critical and unexpected results. First, we determined that the impact of diet on adipose lipid composition and metabolism is under strict control of adipose lipid chaperones and that these molecules ensure that dietary input is the predominant determinant of fatty acid composition in fat. In the absence of these proteins, adipose tissue is markedly refractory to the effects of diet on its lipid constituency and relies heavily on de novo lipogenesis. Second, we have demonstrated that adipose tissue regulates, in a lipid chaperone-dependent manner, the metabolic activities of distant organs through its lipid output and reduced this to a specific metabolic pathway in the liver. Third, we identified a unique fatty acid, C16:1n7-palmitoleate, as a major signaling lipid hormone that controls several metabolic activities in liver and muscle tissues. Finally, these studies have allowed us to derive a model of the molecular mechanisms underlying the biology of lipid chaperones and how these molecules regulate an adipose-derived lipid hormone to generate their remarkable systemic effects.
How de novo
lipogenesis in adipose tissue is affected by metabolic syndrome has remained an unresolved issue. Emerging evidence has suggested that adipose tissue has reduced lipid synthesis capacity in obese mice and human beings (Moraes et al., 2003
; Nadler et al., 2000
). Additionally, genetic or pharmacological manipulations that boost de novo
lipogenesis in adipose tissue (even though this sometimes leads to expansion of the fat depot) are associated with improved metabolic homeostasis (Kuriyama et al., 2005
; Waki et al., 2007
), and outcomes that are very different from those caused by dietary obesity (Kim et al., 2007
; Watkins et al., 2002
). One explanation for this is likely to be related to the differences in tissue and serum fatty acid profiles under the two obese conditions. The systemic approaches employed in our study demonstrated that in WT animals, consuming a HFD resulted in increased lipid content of adipose tissue and the composition of this tissue did not differ from those of muscle or liver as the same lipids contributed to the systemic circulation. In contrast, enhanced de novo
lipogenesis in adipose tissue, which occurs in the absence of lipid chaperons, actively alters tissue and serum fatty acids, particularly palmitoleate, contributing to improved metabolic homeostasis regardless of the total lipid mass.
Our results also raise the possibility that palmitoleate is a major signaling lipid produced from adipose tissue. Several properties of this particular fatty acid fit well into a regulatory role as an adipose tissue-derived hormone. For example, even though fatty acids of all chain lengths and saturation are produced as intermediate products, only palmitoleate is significantly and abundantly accumulated by elevated de novo lipogenesis in adipose tissue. This is potentially due to enzymatic specificity of FAS and coordinated regulation of SCD-1. As a result, palmitoleate might be the only fatty acid that could substantially change serum fatty acid composition in relation to alterations in lipid metabolism in adipose tissue. Unlike its saturated counterpart palmitate, which is already highly enriched in the sn-1 position of phospholipids and triglycerides and is resistant to further enrichment, newly synthesized palmitoleate can be efficiently incorporated into different lipid classes and dramatically alter its enrichment in a variety of compartments. The low basal levels and rapid fluctuations reflecting de novo lipogenesis again support the notion that palmitoleate is suitable to serve as a regulatory signal or a hormone. This characteristic also distinguishes palmitoleate from oleate, which is very abundant in most tissues and rarely exhibits substantial concentration changes under normal physiological conditions. Hence, palmitoleate has the capacity to serve as a lipid signal that mediates communications between adipose and other tissues and we suggest that it be considered a “lipokine” ().
The highly coordinated regulation of lipid flux and metabolism suggests that adipose-specific activation of de novo
lipogenesis might lead to a beneficial general metabolic profile through its systemic effects. If the increased products of lipogenesis in adipose tissue can efficiently suppress liver lipid production, the net outcome of adipose-specific activation of de novo
lipogenesis would be anticipated to be decreased total body weight with improved metabolic profiles. This scenario is in contrast to enhanced lipogenesis in liver which often increases overall adiposity even though both conditions could have elevated serum palmitoleate (Paillard et al., 2007
). This adipose-controlled lipid profile is observed in FABP−/−
mice which exhibit markedly increased palmitoleate in blood and striking protection against metabolic disease along with the benefits of SCD-1 activation in the adipose tissue to convert toxic saturated fatty acids to unsaturated ones. If similar patterns could be extrapolated to humans, compositional studies might offer new biomarkers to monitor disease susceptibility, guide preventive strategies and even lead to clinical interventions using naturally occurring lipid products (Hiraoka-Yamamoto et al., 2004