Febs Letters

doi: 10.1016/S0014-5793(07)01261-6pmid: N/A

Nagy, Laszlo

doi: 10.1016/j.febslet.2007.12.009pmid: N/A

Sonoda, Junichiro; Pei, Liming; Evans, Ronald M.

doi: 10.1016/j.febslet.2007.11.016pmid: 18023286

Nuclear receptors (NR) are a superfamily of ligand‐activated transcription factors that regulate development, reproduction, and metabolism of lipids, drugs and energy. The importance of this family of proteins in metabolic disease is exemplified by NR ligands used in the clinic or under exploratory development for the treatment of diabetes mellitus, dyslipidemia, hypercholesterolemia, or other metabolic abnormalities. Genetic studies in humans and rodents support the notion that NRs control a wide variety of metabolic processes by regulating the expression of genes encoding key enzymes, transporters and other proteins involved in metabolic homeostasis. Current knowledge of complex NR metabolic networks is summarized here.

Zhang, Yanqiao; Edwards, Peter A.

doi: 10.1016/j.febslet.2007.11.015pmid: 18023284

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has been shown to be important in controlling numerous metabolic pathways; these include roles in maintaining bile acid, lipid and glucose homeostasis, in preventing intestinal bacterial infection and gallstone formation and in modulating liver regeneration and tumorigenesis. The accumulating data suggest that FXR may be a pharmaceutical target for the treatment of certain metabolic diseases.

Duez, Hélène; Staels, Bart

doi: 10.1016/j.febslet.2007.08.032pmid: 17765229

Normal physiological processes are under control of circadian rhythms. Moreover, certain pathological events, such as cardiovascular accidents (myocardial infarction, stroke) occur more frequently at specific times of the day. Recent observations demonstrate a causal relationship between alterations in circadian rhythmicity and metabolic disorders. Disruption of clock genes results in dyslipidemia, insulin resistance and obesity, all predisposing to atherosclerosis. The nuclear receptor Rev‐erbα is part of the clock circuitry and plays an important role in keeping proper timing of the clock. Rev‐erbα also regulates lipid metabolism, adipogenesis and vascular inflammation. Interestingly, Rev‐erbα also cross‐talks with several other nuclear receptors involved in energy homeostasis. Therefore Rev‐erbα may serve to couple metabolic and circadian signals.

Reilly, Shannon M.; Lee, Chih-Hao

doi: 10.1016/j.febslet.2007.11.040pmid: 18036566

PPARδ is the only member in the PPAR subfamily of nuclear receptors that is not a target of current drugs. Animal studies demonstrate PPARδ activation exerts many favorable effects, including reducing weight gain, increasing skeletal muscle metabolic rate and endurance, improving insulin sensitivity and cardiovascular function and suppressing atherogenic inflammation. These activities stem largely from the ability of PPARδ to control energy balance, reduce fat burden and protect against lipotoxicity caused by ectopic lipid deposition. Therefore, PPARδ represents a novel therapeutic target and the development of PPARδ gonists/modulators may be useful for treating the whole spectrum of metabolic syndrome.

Ziouzenkova, Ouliana; Plutzky, Jorge

doi: 10.1016/j.febslet.2007.11.081pmid: 18068127

Retinoids, naturally‐occurring vitamin A derivatives, regulate metabolism by activating specific nuclear receptors, including the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). RXR, an obligate heterodimeric partner for other nuclear receptors, including peroxisome proliferator‐activated receptors (PPARs), helps coordinate energy balance. Recently, many groups have identified new connections between retinoid metabolism and PPAR responses. We found that retinaldehyde (Rald), a molecule that can yield RA through the action of retinaldehyde dehydrogenases (Raldh), is present in fat in vivo and can inhibit PPARγ‐induced adipogenesis. In vitro, Rald inhibits RXR and PPARγ activation. Raldh1‐deficient mice have increased Rald levels in fat, higher metabolic rates and body temperatures, and are protected against diet‐induced obesity and insulin resistance. Interestingly, one specific asymmetric β‐carotene cleavage product, apo‐14′‐carotenal, can also inhibit PPARγ and PPARα responses. These data highlight how pathways of β‐carotene metabolism and specific retinoid metabolites may have direct distinct metabolic effects.

White, Roger; Morganstein, Daniel; Christian, Mark; Seth, Asha; Herzog, Birger; Parker, Malcolm G.

doi: 10.1016/j.febslet.2007.11.017pmid: 18023280

The control of physiological processes requires the regulation and coordination of many different signals and is determined in part by the activation and repression of expression of specific target genes. RIP140 is a ligand dependent coregulator of many nuclear receptors that influence such diverse processes as muscle metabolism, adipocyte and hepatocyte function, and reproduction. Recent evidence has shown that the ability of RIP140 to regulate nuclear receptor function is determined by the relative level of RIP140 expression in comparison with other cofactors, by post‐translational modifications and by interactions with additional transcription factors. As a result it is becoming apparent that RIP140, via its interplay with other coregulators, plays a fundamental role in determining both the normal and pathogenic physiological state.

Rodgers, Joseph T.; Lerin, Carles; Gerhart-Hines, Zachary; Puigserver, Pere

doi: 10.1016/j.febslet.2007.11.034pmid: 18036349

Energy homeostasis in mammals is achieved through tight regulation of tissue‐specific metabolic pathways that become dysregulated in metabolic diseases including diabetes and obesity. At the molecular level, main nutrient and hormonal signaling pathways impinge on expression of genes encoding for metabolic enzymes. Among the major components of this transcriptional circuitry are the PGC‐1α transcriptional complexes. An important regulatory mechanism of this complex is through acetylation and SIRT1‐mediated lysine de‐acetylation under low nutrient conditions. Activation of SIRT1 can mimic several metabolic aspects of calorie restriction that target selective nutrient utilization and mitochondrial oxidative function to regulate energy balance. Thus, understanding the PGC‐1α and SIRT1 pathways might have important implications for comprehending metabolic and age‐associated diseases.

Nakae, Jun; Oki, Miyo; Cao, Yongheng

doi: 10.1016/j.febslet.2007.11.025pmid: 18022395

Forkhead transcription factors FoxOs are conserved beyond species and regulated by insulin signaling pathway. FoxOs have diverse functions on differentiation, proliferation and cell survival. In calorie restriction (CR) or starvation, FoxOs are in nucleus, active transcriptionally, and increase hepatic glucose production, decrease insulin secretion, increase food intake and cause degradation of skeletal muscle for supplying substrates for glucose production. However, even in insulin resistance due to excessive calorie intake, FoxOs are active and causes type 2 diabetes and hyperlipidemia. The understanding of molecular mechanism how FoxOs affect glucose or lipid metabolism will shed light on the novel therapy of type 2 diabetes and the metabolic syndrome.