Early detection of risk factors for enhanced primary prevention and novel therapies for treating the chronic consequences of cardiovascular disease are of the utmost importance for reducing morbidity. Recently, fibroblast growth factors (FGFs) have been intensively studied as potential new molecules in the prevention and treatment of cardiovascular disease mainly attributable to metabolic effects and angiogenic actions. Members of the endocrine FGF family have been shown to increase metabolic rate, decrease adiposity, and restore glucose homeostasis, suggesting a multiple metabolic role. Serum levels of FGFs have been associated with established cardiovascular risk factors as well as with the severity and extent of coronary artery disease and could be useful for prediction of cardiovascular death. Furthermore, preclinical investigations and clinical trials have tested FGF administration for therapeutic angiogenesis in ischemic vascular disease, demonstrating a potential role in improving angina and limb function. FGF21 has lately emerged as a potent metabolic regulator with multiple effects that ultimately improve the lipoprotein profile. Early studies show that FGF21 is associated with the presence of atherosclerosis and may play a protective role against plaque formation by improving endothelial function. The present review highlights recent investigations suggesting that FGFs, in particular FGF21, may be useful as markers of cardiovascular risk and may also serve as protective/therapeutic agents in cardiovascular disease.

Fibroblast growth factor 21 (FGF21) was originally identified as a member of the FGF family in homology studies and is a member of the endocrine FGF subfamily that lacks heparin binding domains and is released into the circulation. A potential role as a metabolic regulator emerged when FGF21 was shown to increase glucose uptake in adipocytes. Subsequently, marked elevations in FGF21 expression were observed in mice that ate a ketogenic diet and when fasting, which suggests that FGF21 expression plays a role in the adaptation to metabolic states that require increased fatty acid oxidation. Consistent with this evidence, FGF21 knockout mice were not able to respond appropriately to consumption of a ketogenic diet. FGF21 expression is downstream of peroxisome proliferatoractivated receptor (PPAR) a in the liver and PPARc in adipose tissue. FGF21 concentrations are higher in both rodent and human obesity, and recent data suggest that obesity may be an FGF21-resistant state. Recent data increasingly suggest that FGF21 is an important metabolic regulator that may have potential clinical implications.Am J Clin Nutr 2011;93(suppl):901S-5S.

Melanin-concentrating hormone (MCH) is an orexigenic hypothalamic neuropeptide. At least one receptor, MCH receptor 1 (MCHR1), is present in all mammals and is expressed widely throughout the brain, including cortex, striatum and structures implicated in the integration of olfactory cues such as the piriform cortex and olfactory bulb. Consistent with a potential role for MCH in mediating olfactory function, MCH knockout mice demonstrate abnormal olfactory behaviors. These behaviors include impaired food seeking by both genders while maintaining normal levels of locomotion, suggesting impaired olfaction. Males also exhibit increased aggression while females show defects in several olfactory mediated behaviors including mating, estrous cycle synchronization and maternal behavior. These findings suggest that hypothalamic inputs through MCH play an important role in regulating sensory integration from olfactory pathways.

Thyroid hormone (TH) regulates fibroblast growth factor 21 (FGF21) levels in the liver and in the adipose tissue. In contrast, peripheral FGF21 administration leads to decreased circulating levels of TH. These data suggest that FGF21 and TH could interact to regulate metabolism. In the present study, we confirmed that TH regulates adipose and hepatic FGF21 expression and serum levels in mice. We next investigated the influence of TH administration on key serum metabolites, gene expression in the liver and brown adipose tissue, and energy expenditure in FGF21 knockout mice. Surprisingly, we did not observe any significant differences in the effects of TH on FGF21 knockout mice compared with those in wild-type animals, indicating that TH acts independently of FGF21 for the specific outcomes studied. Furthermore, exogenous FGF21 administration to hypothyroid mice led to similar changes in serum and liver lipid metabolites and gene expression in both hypothyroid and euthyroid mice. Thus, it appears that FGF21 and TH have similar actions to decrease serum and liver lipids despite having some divergent regulatory effects. Whereas TH leads to up-regulation in the liver and down-regulation in brown adipose tissue of genes involved in the lipid synthesis pathway (eg, fatty acid synthase (FASN) and SPOT14), FGF21 leads to the opposite changes in expression of these genes. In conclusion, TH and FGF21 act independently on the outcomes studied, despite their ability to regulate each other's circulating levels. Thus, TH and FGF21 may modulate the availability of each other in critical metabolic states.