Gastric GDF15 levels are regulated by age, sex, and nutritional status in rodents and humans.

AIM: Growth differentiation factor 15 (GDF15) is a stress response cytokine that has been proposed as a relevant metabolic hormone. Descriptive studies have shown that plasma GDF15 levels are regulated by short term changes in nutritional status, such as fasting, or in obesity. However, few data exist regarding how GDF15 levels are regulated in peripheral tissues. The aim of the present work was to study the variations on gastric levels of GDF15 and its precursor under different physiological conditions, such as short-term changes in nutritional status or overfeeding achieved by HFD. Moreover, we also address the sex- and age-dependent alterations in GDF15 physiology. METHODS: The levels of gastric and plasma GDF15 and its precursor were measured in lean and obese mice, rats and humans by western blot, RT-PCR, ELISA, immunohistochemistry and by an in vitro organ culture system. RESULTS: Our results show a robust regulation of gastric GDF15 production by fasting in rodents. In obesity an increase in GDF15 secretion from the stomach is reflected with an increase in circulating levels of GDF15 in rats and humans. Moreover, gastric GDF15 levels increase with age in both rats and humans. Finally, gastric GDF15 levels display sexual dimorphism, which could explain the difference in circulating GFD15 levels between males and females, observed in both humans and rodents. CONCLUSIONS: Our results provide clear evidence that gastric GDF15 is a critical contributor of circulating GDF15 levels and can explain some of the metabolic effects induced by GDF15.

Olanzapine depot exposure in male rats: Dose-dependent lipogenic effects without concomitant weight gain.

Treatment with second-generation antipsychotic agents such as olanzapine frequently results in metabolic adverse effects, e.g. hyperphagia, weight gain and dyslipidaemia in patients of both genders. The molecular mechanisms underlying metabolic adverse effects are still largely unknown, and studies in rodents represent an important approach in their exploration. However, the validity of the rodent model is hampered by the fact that antipsychotics induce weight gain in female, but not male, rats. When administered orally, the short half-life of olanzapine in rats prevents stable plasma concentrations of the drug. We recently showed that a single intramuscular injection of long-acting olanzapine formulation yields clinically relevant plasma concentrations accompanied by several dysmetabolic features in the female rat. In the current study, we show that depot injections of 100-250 mg/kg olanzapine yielded clinically relevant plasma olanzapine concentrations also in male rats. In spite of transient hyperphagia, however, olanzapine resulted in weight loss rather than weight gain. The resultant negative feed efficiency was accompanied by a slight elevation of thermogenesis markers in brown adipose tissue for the highest olanzapine dose, but the olanzapine-related reduction in weight gain remains to be explained. In spite of the absence of weight gain, an olanzapine dose of 200mg/kg or above induced significantly elevated plasma cholesterol levels and pronounced activation of lipogenic gene expression in the liver. These results confirm that olanzapine stimulates lipogenic effects, independent of weight gain, and raise the possibility that endocrine factors may influence gender specificity of metabolic effects of antipsychotics in the rat.

Hypothalamic mTOR: the rookie energy sensor.

Optimal cellular function and therefore organism's survival is determined by the sensitive and accurate convergence of energy and nutrient abundance to cell growth and division. Among other factors, this integration is coupled by the target of rapamycin (TOR) pathway, which is able to sense nutrient, energy and oxygen availability and also growth factor signaling. Indeed, TOR signaling regulates cell energy homeostasis by coordinating anabolic and catabolic processes for survival. TOR, named mTOR in mammals, is a conserved serine/threonine kinase that exists in two different complexes, mTORC1 and mTORC2. Recently, studies are suggesting that alterations of those complexes promote disease and disrupted phenotypes, such as aging, obesity and related disorders and even cancer. The evidences linking mTOR to energy and metabolic homeostasis included the following. At central level mTOR regulates food intake and body weight being involved in the mechanism by which signals such as leptin and ghrelin exert its effects. At peripheral level it influences adipogenesis and lipogenesis in different tissues including the liver. Noteworthy chronic nutritional activation of mTOR signaling has been implicated in the development of beta cell mass expansion and on insulin resistance. Understanding of mTOR and other molecular switches, such as AMP-activated protein kinase (AMPK), as well as their interrelationship is crucial to know how organisms maintain optimal homeostasis. This review summarizes the role of hypothalamic TOR complex in cellular energy sensing, evidenced in the last years, focusing on the metabolic pathways where it is involved and the importance of this metabolic sensor in cellular and whole body energy management. Understanding the exact role of hypothalamic mTOR may provide new cues for therapeutic intervention in diseases.

Association study of energy homeostasis genes and antipsychotic-induced weight gain in patients with schizophrenia.

INTRODUCTION: Marked inter-individual variation has been observed with respect to the risk of weight gain and related metabolic disturbances during antipsychotic treatment, which in part could be explained by heritability. Such adverse effects have been proposed to occur through drug-induced mechanisms involving both the central nervous system and different peripheral tissues. METHODS: We genotyped tagSNPs in several genes ( ADIPOQ, PRKAA1, PRKAA2, PRKAB1, PRKAG1, PRKAG2, PRKAG3, FTO and FABP3) that regulate lipid and energy homeostasis for their possible association to antipsychotic-induced weight gain. RESULTS: In a sample of 160 patients of German origin with schizophrenia who had been monitored with respect to body weight, we found marked association between antipsychotic-related changes in BMI and 6 markers in the adiponectin gene ( ADIPOQ). DISCUSSION: These findings support previous observations (in patients' serum) that adiponectin is involved in antipsychotic-mediated metabolic adverse effects.

Polymorphisms in SREBF1 and SREBF2, two antipsychotic-activated transcription factors controlling cellular lipogenesis, are associated with schizophrenia in German and Scandinavian samples.

Several studies have reported structural brain abnormalities, decreased myelination and oligodendrocyte dysfunction in schizophrenia. In the central nervous system, glia-derived de novo synthesized cholesterol is essential for both myelination and synaptogenesis. Previously, we demonstrated in glial cell lines that antipsychotic drugs induce the expression of genes involved in cholesterol and fatty acids biosynthesis through activation of the sterol regulatory element binding protein (SREBP) transcription factors, encoded by the sterol regulatory element binding transcription factor 1 (SREBF1) and sterol regulatory element binding transcription factor 2 (SREBF2) genes. Considering the importance of these factors in the lipid biosynthesis and their possible involvement in antipsychotic drug effects, we hypothesized that genetic variants of SREBF1 and/or SREBF2 could affect schizophrenia susceptibility. We therefore conducted a HapMap-based association study in a large German sample, and identified association between schizophrenia and five markers in SREBF1 and five markers in SREBF2. Follow-up studies in two independent samples of Danish and Norwegian origin (part of the Scandinavian collaboration of psychiatric etiology study, SCOPE) replicated the association for the five SREBF1 markers and for two markers in SREBF2. A combined analysis of all samples resulted in highly significant genotypic P-values of 9 x 10(-4) for SREBF1 (rs11868035, odd ration (OR)=1.26, 95% confidence interval (CI) (1.09-1.45)) and 4 x 10(-5) for SREBF2 (rs1057217, OR=1.39, 95% CI (1.19-1.63)). This finding strengthens the hypothesis that SREBP-controlled cholesterol biosynthesis is involved in the etiology of schizophrenia.

Association between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects?

Atypical antipsychotics are nowadays the most widely used drugs to treat schizophrenia and other psychosis. Unfortunately, some of them can cause major metabolic adverse effects, such as weight gain, dyslipidemia and type 2 diabetes. The underlying lipogenic mechanisms of the antipsychotic drugs are not known, but several studies have focused on a central effect in the hypothalamic control of appetite regulation and energy expenditure. In a functional convergent genomic approach we recently used a cellular model and demonstrated that orexigenic antipsychotics that induce weight gain activate the expression of lipid biosynthesis genes controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We therefore hypothesized that the major genes involved in the SREBP activation of fatty acids and cholesterol production (SREBF1, SREBF2, SCAP, INSIG1 and INSIG2) would be strong candidate genes for interindividual variation in drug-induced weight gain. We genotyped a total of 44 HapMap-selected tagging single nucleotide polymorphisms in a sample of 160 German patients with schizophrenia that had been monitored with respect to changes in body mass index during antipsychotic drug treatment. We found a strong association (P=0.0003-0.00007) between three markers localized within or near the INSIG2 gene (rs17587100, rs10490624 and rs17047764) and antipsychotic-related weight gain. Our finding is supported by the recent involvement of the INSIG2 gene in obesity in the general population and implicates SREBP-controlled lipogenesis in drug-induced metabolic adverse effects.

Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action?

Several studies have reported on structural abnormalities, decreased myelination and oligodendrocyte dysfunction in post-mortem brains from schizophrenic patients. Glia-derived cholesterol is essential for both myelination and synaptogenesis in the CNS. Lipogenesis and myelin synthesis are thus interesting etiological candidate targets in schizophrenia. Using a microarray approach, we here demonstrate that the antipsychotic drugs clozapine and haloperidol upregulate several genes involved in cholesterol and fatty acid biosynthesis in cultured human glioma cells, including HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase), HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase-1), FASN (fatty acid synthase) and SCD (stearoyl-CoA desaturase). The changes in gene expression were followed by enhanced HMGCR-enzyme activity and elevated cellular levels of cholesterol and triglycerides. The upregulated genes are all known to be controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We show that clozapine and haloperidol both activate the SREBP system. The antipsychotic-induced SREBP-mediated increase in glial cell lipogenesis could represent a novel mechanism of action, and may also be relevant for the metabolic side effects of antipsychotics.