Energy-responsive timekeeping.

An essential component of energy homeostasis lies in an organism's ability to coordinate daily patterns in activity, feeding, energy utilization and energy storage across the daily 24-h cycle. Most tissues of the body contain the molecular clock machinery required for circadian oscillation and rhythmic gene expression. Under normal circumstances, behavioural and physiological rhythms are orchestrated and synchronized by the suprachiasmatic nucleus (SCN) of the hypothalamus, considered to be the master circadian clock. However, metabolic processes are easily decoupled from the primarily light-driven SCN when food intake is desynchronized from normal diurnal patterns of activity. This dissociation from SCN based timing demonstrates that the circadian system is responsive to changes in energy supply and metabolic status. There has long been evidence for the existence of an anatomically distinct and autonomous food-entrainable oscillator (FEO) that can govern behavioural rhythms, when feeding becomes the dominant entraining stimulus. But now rapidly growing evidence suggests that core circadian clock genes are involved in reciprocal transcriptional feedback with genetic regulators of metabolism, and are directly responsive to cellular energy supply. This close interaction is likely to be critical for normal circadian regulation of metabolism, and may also underlie the disruption of proper metabolic rhythms observed in metabolic disorders, such as obesity and type-II diabetes.

PPARs, síndrome metabólico y enfermedad cardíaca / PPARs, metabolic syndrome and cardiac diseases

The nuclear receptor PPARs (peroxisomal proliferators-activated receptors) are transcription factors activated by natural and synthetic ligands. Three different isoforms of PPARs have been described, PPARalpha, PPARbeta/ delta, and PPARgamma. PPARs isoforms are tissue-dependent expressed and they regulate the gene expression of proteins involved in glucose and lipid metabolism. Selective pharmacological activation of these isoforms has revealed their role in cellular physiology. Nowadays, two kinds of PPARs agonists are currently used in the clinical practice, the fibrate hypolipidemic drugs, used in the treatment of dyslipidemia, are synthetic ligands for PPARalpha, whereas thiazolidinediones or glitazones have PPARgamma selectivity and are used as hypoglycemic agents. The main cellular effect of PPAR activation lies on fatty acid oxidation and mobilization (PPARalpha) as well as they act as insulin sensitizers on peripheral tissues (PPARgamma). In addition to these beneficial effects of PPARs, it has also been demonstrated that PPARs activation can prevent cardiac dysfunction in diabetic patients as well as the anti-inflammatory processes developed in many diseases. Recent development of PPARbeta/delta and hybrid PPARs alpha and gamma agonists, and their clinical trials are giving promising outcomes in the therapeutics of metabolic syndrome, diabetes and cardiac diseases.

Glitazonas e síndrome metabólica: mecanismos de ação, fisiopatologia e indicações terapêuticas / Glitazones and the metabolic syndrome: mechanism of action, pathophysiology and therapeutic indications

O diabetes mellitus (DM) é considerado um problema de saúde pública em países devido às suas complicações crônicas macro e microvasculares, com grande impacto na morbimortalidade dos pacientes. A doença é o estágio final de uma síndrome crônica e progressiva, cujas anormalidades fisiopatológicas iniciam-se anos antes do diagnóstico clínico da doença. A síndrome metabólica (SM) é conseqüente ao aumento mundial da prevalência de obesidade. O DM é freqüentemente associado com condições clínicas e laboratoriais que fazem parte da SM, como a obesidade, hipertensão arterial, dislipidemia e microalbuminúria, também fatores de risco cardiovascular. Estudos populacionais demonstram aumento na prevalência de todos os fatores que compõem esta síndrome do pré-diabetes ao DM manifesto, resultando em elevada prevalência de doença cardiovascular e morbimortalidade. Estima-se que >80 por cento dos pacientes com DM apresentem SM. As glitazonas são agonistas PPAR-gama que melhoram a sensibilidade insulínica. Estas drogas induzem à transcrição de genes relacionados ao metabolismo glicídico e lipídico e à expressão de proteínas inflamatórias e endoteliais associadas com o processo aterosclerótico, resultando em melhora da função endotelial. Entretanto, algumas questões relacionadas às glitazonas merecem mais estudos, como a causa de seus efeitos colaterais (ganho de peso, edema e desenvolvimento de insuficiência cardíaca congestiva).

Diabetes mellitus (DM) is considered a major public health problem in both developed and developing countries due to its chronic complications, at the macro or microcirculation, with great impact on mortality and morbidity in all patients. The disease is considered the end of a pathophysiologic process involving peripheral and hepatic insulin resistance and reduced insulin secretion that have been started years before the clinical diagnosis. Metabolic syndrome (MS) is a disorder that results from the increasing prevalence of obesity worldwide. DM is frequently associated with clinical and laboratory features of MS, like abdominal obesity, hypertension, dyslipidemia and microalbuminuria that are also risk factors for cardiovascular disease. Populational studies have demonstrated increasing prevalence of all the features of MS from pre-diabetes to clinical DM resulting in a great risk of cardiovascular disease. The prevalence of MS in DM type 2 is estimated to be >80 percent. Glitazones are PPAR-gamma agonists that improve insulin sensitivity. These drugs induce the transcription of genes related to glucose and lipid metabolism, and expression of inflammatory and endothelial proteins associated with atherosclerosis process resulting in an improvement in endothelial function. However several questions need to be clarified regarding the glitazones, in special those associated with their adverse effects such as weight gain, edema and heart failure.

Adipocyte Signals in Energy Balance and Digestive Diseases / 대한소화기학회지

For the regulation of energy balance in various internal organs including gut, pancreas and liver, visceral adipose tissue and brain perform important sensing and signaling roles via neural and endocrine pathway. Among these, adipose tissue has been known as a simple energy-storing organ, which stores excess energy in triglyceride. However, it became apparent that adipocytes have various receptors related to energy homeostasis, and secrete adipocytokines by endocrine, paracrine and autocrine mechanisms. In this review, basic roles of adipocytes in energy homeostasis and the correlation between adipocyte signals and digestive diseases are discussed.