Fernando Lizcano

Biology of Beige Adipocyte and Possible Therapy for Type 2 Diabetes and Obesity

All mammals own two main forms of fat. The classical white adipose tissue builds up energy in the form of triglycerides and is useful for preventing fatigue during periods of low caloric intake and the brown adipose tissue instead of inducing fat accumulation can produce energy as heat. Since adult humans possess significant amounts of active brown fat depots and their mass inversely correlates with adiposity, brown fat might play an important role in human obesity and energy homeostasis. New evidence suggests two types of thermogenic adipocytes with distinct developmental and anatomical features: classical brown adipocytes and beige adipocytes. Beige adipocyte has recently attracted special interest because of its ability to dissipate energy and the possible ability to differentiate itself from white adipocytes. Importantly, adult human brown adipocyte appears to be mainly composed of beige-like adipocytes, making this cell type an attractive therapeutic target for obesity and obesity-related diseases. Because many epigenetic changes can affect beige adipocyte differentiation, the knowledge of the circumstances that affect the development of beige adipocyte cells may be important for therapeutic strategies. In this review we discuss some recent observations arising from the great physiological capacity of these cells and their possible role as ways to treat obesity and diabetes mellitus type 2.

Consenso latino-americano de hipertensão em pacientes com diabetes tipo 2 e síndrome metabólica

The present document has been prepared by a group of experts, members of cardiology, endocrinology, internal medicine, nephrology and diabetes societies of Latin American countries, to serve as a guide to physicians taking care of patients with diabetes, hypertension and comorbidities or complications of both conditions. Although the concept of metabolic syndrome is currently disputed, the higher prevalence in Latin America of that cluster of metabolic alterations has suggested that metabolic syndrome is a useful nosography entity in the context of Latin American medicine. Therefore, in the present document, particular attention is paid to this syndrome in order to alert physicians on a particular high-risk population, usually underestimated and undertreated. These recommendations result from presentations and debates by discussion panels during a 2-day conference held in Bucaramanga, in October 2012, and all the participants have approved the final conclusions. The authors acknowledge that the publication and diffusion of guidelines do not suffice to achieve the recommended changes in diagnostic or therapeutic strategies, and plan suitable interventions overcoming knowledge, attitude and behavioural barriers, preventing both physicians and patients from effectively adhering to guideline recommendations. Arq Bras Endocrinol Metab. 2014;58(3):205-25

Epigenetic Control and Cancer: The Potential of Histone Demethylases as Therapeutic Targets

The development of cancer involves an immense number of factors at the molecular level. These factors are associated principally with alterations in the epigenetic mechanisms that regulate gene expression profiles. Studying the effects of chromatin structure alterations, which are caused by the addition/removal of functional groups to specific histone residues, are of great interest as a promising way to identify markers for cancer diagnosis, classify the disease and determine its prognosis, and these markers could be potential targets for the treatment of this disease in its different forms. This manuscript presents the current point of view regarding members of the recently described family of proteins that exhibit histone demethylase activity; histone demethylases are genetic regulators that play a fundamental role in both the activation and repression of genes and whose expression has been observed to increase in many types of cancer. Some fundamental aspects of their association with the development of cancer and their relevance as potential targets for the development of new therapeutic strategies at the epigenetic level are discussed in the following manuscript.

EID1-induces brown-like adipocyte traits in white 3T3-L1 pre-adipocytes.

PPARgamma and pRB play an important role in the development of adipose cells, and functional modification of these proteins may lead to beneficial changes in adipose cell physiology. In the present work, we show that over-expression of EID1 (E1A-like inhibitor of differentiation), an inhibitor of muscle cell differentiation, reduces PPARgamma ligand-dependent transactivation and decreases triglyceride stores in pre-adipocytes (3T3-L1 cells). Additionally, we found that EID1 binds to pRB at the onset of adipocyte differentiation and may act to reduce pRB levels. Over-expression of EID1 in 3T3-L1 cells leads to increased expression of UCP1 and PGC-1alpha, both of which are involved in caloric dissipation and thermogenesis, in brown adipose tissue. These results indicate that EID1 is able to reduce fat accumulation in adipose cells and induce expression of brown fat genes in pre-adipocytes (3T3-L1 cells) normally destined to become white fat cells. The functional reduction of PPARgamma and pRB mediated by EID1 in adipose cells may play an important role in insulin resistance and the metabolic syndrome.

Cell type-specific roles of histone deacetylase in TR ligand-independent transcriptional repression

Recent evidence indicates that corepressor protein with histone deacetylase (HDAC) activity mediates thyroid hormone receptor (TR) transcriptional repression. In order to examine the physiological relevance of HDAC in ligand-independent TR-mediated repression, we studied the effect of trichostatin A (TSA), a specific HDAC inhibitor, in transient transfection studies with natural reporters, and assessed the expression of TR-regulated endogenous genes. Luciferase-coupled DR4-, F2-, PAL- or GH-TREs and TRbeta1 expression vectors were cotransfected in CV-1 and GH(3) cells. We did not observe any effect of TSA on TR-induced basal repression in CV-1 cells. Instead, TSA was able to induce an increase in transcription without T(3) on all TREs tested in GH(3) cells. This increase was >7-fold on F2-, >4-fold on DR4-, and 3-fold on GH-TREs. The cotransfection of a TRbeta1 mutant that exhibits decreased affinity with N-CoR (AHT) reduced the TSA effect in GH(3) cells, demonstrating a primary role for TR/N-CoR/Sin3/HDAC complex. Next, we examined the effects of TSA on endogenous GH mRNA production in GH(3) cells by Northern blot analysis. We observed an increase of 50-70% of GH mRNA in cells treated with TSA in hypothyroid medium, and an increase of GH mRNA in T(3)-treated cells after TSA treatment. Our results show that TSA can increase the expression of endogenous genes that are susceptible to TR regulation. These results support an active role of HDAC in transcriptional repression by ligand-independent TR.

Advances in Gut Microbiome Research, Opening New Strategies to Cope with a Western Lifestyle

The “westernization” of global eating and lifestyle habits is associated with the growing rate of chronic diseases, mainly cardiovascular diseases, cancer, type 2 diabetes mellitus, and respiratory diseases. The primary prevention approach is to make nutritional and behavioral changes, however, there is another important determinant of our health that only recently has been considered and is the presence of beneficial microorganisms and their products in our gastrointestinal tract. Microorganisms living in our body can alter the fate of food, drugs, hormones, and xenobiotics, and recent studies point to the use of microorganisms that can counteract the harmful effects of certain compounds introduced or produced endogenously in our body. This review considers the effects of the western lifestyle on adiposity, glucose metabolism, oxidative markers and inflammation profile, emphasizes on the studies that have investigated bacterial strains and products of their metabolism that are beneficial under this lifestyle, and examines the screening strategies that recent studies are using to select the most promising probiotic isolates. In addition, we consider the relevance of studying the microbiota of metabolically healthy people under a western lifestyle for the understanding of the key components that delay the development of chronic diseases.

Modifications of Human Subcutaneous ADMSC after PPARγ Activation and Cold Exposition

Mesenchymal stem cells are a diverse population of cells with a wide range of potential therapeutic applications. In particular, cells from adipose tissue have the distinction of being easily accessible and contain a lot of stem cells. ADMSCs can be induced to mature adipocyte and activate the energy expenditure upon treatment with total PPARγ agonists. Additionally these cells may respond to cold by activating the thermogenic program. In the present study, we determined the effect of partial agonism of PPARγ and temperature reduction on phenotype and metabolic activity of ADMSCs from human adipose subcutaneous tissue. We found that adipocytes differentiated with total and partial agonists of PPARγ and exposed to 31°C are able to respond to cold significantly increasing the expression of thermogenic proteins such as UCP1, PGC1α, and CITED1, a marker of beige phenotype. Additionally, we found that adipocyte cells subjected to cold had a reduction in triglycerides and increased adiponectin levels. These data confirm the promising role of ADMSCs as a treatment for metabolic disorders since it is possible to induce them to mature adipocytes and modulate their phenotype toward a cell with high-energy expenditure and metabolic beneficial effect.

Consenso latinoamericano de hipertensión en pacientes con diabetes tipo 2 y síndrome metabólico

The present document has been prepared by a group of experts, members of Cardiology, Endocrinology, Internal Medicine, Nephrology and Diabetes societies of Latin American countries, to serve as a guide to physicians taking care of patients with diabetes, hypertension and comorbidities or complications of both conditions. Although the concept of metabolic syndrome is currently disputed, the higher prevalence in Latin America of that cluster of metabolic alterations has suggested that metabolic syndrome is useful nosography entity in the context of Latin American medicine. Therefore, in the present document, particular attention is paid to this syndrome in order to alert physicians on a particular high- risk population, usually underestimated and undertreated. These recommendations results from presentation and debates by discussion panels during a 2-day conference held in Bucaramanga, in October 2012, and all the participants have approved the final conclusions. The authors acknowledge that the publication and diffusion of guidelines do not suffice to achieve the recommended changes in diagnostic or therapeutic strategies, and plan suitable interventions overcoming both physicians and patients from effectively adhering to guideline recommendations.

Diverse coactivator recruitment through differential PPARγ nuclear receptor agonism

The PPARγ nuclear receptor regulates the expression of genes involved in lipid and carbohydrate metabolism, and it has protective effects in some patients with type 2 diabetes. Nevertheless, the therapeutic value of the PPARγ nuclear receptor protein is limited due to the secondary effects of some PPARγ ligands. Because the downstream effects of PPARγ are determined by the binding of specific cofactors that are mediated by ligand-induced conformational changes, we evaluated the differential effects of various ligands on the binding of certain cofactors associated with PPARγ. The ligands used were rosiglitazone for treating type 2 diabetes and telmisartan for treating arterial hypertension. Functional, phenotypic, and molecular studies were conducted on pre-adipocyte 3T3-L1 and functional studies in U2OS cells. The moderating influence of various cofactor families was evaluated using transient transfection assays. Our findings confirm that telmisartan has a partial modulating effect on PPARγ activity compared to rosiglitazone. The cofactors SRC1 and GRIP1 mediate the activity of telmisartan and rosiglitazone and partially determine the difference in their effects. Studying the modulating activity of these cofactors can provide interesting insights for developing new therapeutic approaches for certain metabolic diseases.

Regulation of human subcutaneous adipocyte differentiation by EID1

Increasing thermogenesis in white adipose tissues can be used to treat individuals at high risk for obesity and cardiovascular disease. The objective of this study was to determine the function of EP300-interacting inhibitor of differentiation (EID1), an inhibitor of muscle differentiation, in the induction of beige adipocytes from adipose mesenchymal stem cells (ADMSCs). Subcutaneous adipose tissue was obtained from healthy women undergoing abdominoplasty. ADMSCs were isolated in vitro, grown, and transfected with EID1 or EID1 siRNA, and differentiation was induced after 48 h by administering rosiglitazone. The effects of EID1 expression under the control of the aP2 promoter (aP2-EID1) were also evaluated in mature adipocytes that were differentiated from ADMSCs. Transfection of EID1 into ADMSCs reduced triglyceride accumulation while increasing levels of thermogenic proteins, such as PGC1α, TFAM, and mitochondrial uncoupling protein 1 (UCP1), all of which are markers of energy expenditure and mitochondrial activity. Furthermore, increased expression of the beige phenotype markers CITED1 and CD137 was observed. Transfection of aP2-EID1 transfection induced the conversion of mature white adipocytes to beige adipocytes, as evidenced by increased expression of PGC1α, UCP1, TFAM, and CITED1. These results indicate that EID1 can modulate ADMSCs, inducing a brown/beige lineage. EID1 may also activate beiging in white adipocytes obtained from subcutaneous human adipose tissue.