1. Investigación

Background. Over the last few years, the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) has increased substantially in medical practice due to their documented benefits in cardiorenal and metabolic health. In this sense, and in addition to being used for glycemic control in diabetic patients, these drugs also have other favorable effects such as weight loss and lowering blood pressure, and more recently, they have been shown to have cardio and renoprotective effects with anti-inflammatory properties. Concerning the latter, the individual or associated use of these antihyperglycemic agents has been linked with a decrease in proinflammatory cytokines and with an improvement in the inflammatory profile in chronic endocrine-metabolic diseases. Hence, these drugs have been positioned as first-line therapy in the management of diabetes and its multiple comorbidities, such as obesity, which has been associated with persistent inflammatory states that induce dysfunction of the adipose tissue. Moreover, other frequent comorbidities in long-standing diabetic patients are chronic complications such as diabetic kidney disease, whose progression can be slowed by SGLT2i and/or GLP-1RA. The neuroendocrine and immunometabolism mechanisms underlying adipose tissue inflammation in individuals with diabetes and cardiometabolic and renal diseases are complex and not fully understood. Summary. This review intends to expose the probable molecular mechanisms and compile evidence of the synergistic or additive anti-inflammatory effects of SGLT2i and GLP-1RA and their potential impact on the management of patients with obesity and cardiorenal compromise.

The incidence of obesity and its related disorders has increased dramatically in recent years and has become a pandemic. Adipose tissue is a crucial regulator of these diseases due to its endocrine capacity. Thus, understanding adipose tissue metabolism is essential to finding new effective therapeutic approaches. The “omic” revolution has identified new concepts about the complexity of the signaling pathways involved in the pathophysiology of adipose tissue-associated disorders. Specifically, advances in transcriptomics have allowed its application in clinical practice and primary or secondary prevention. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of adipose tissue since they can modulate gene expression at the epigenetic, transcriptional, and post-transcriptional levels. They interact with DNA, RNA, protein complexes, other noncoding RNAs, and microRNAs to regulate a wide range of physiological and pathological processes. Here, we review the emerging field of lncRNAs, including how they regulate adipose tissue biology, and discuss circulating lncRNAs, which may represent a turning point in the diagnosis and treatment of adipose tissue-associated disorders. We also highlight potential biomarkers of obesity and diabetes that could be considered as therapeutic targets.

Objective: To test whether enhancing the capability of adipose tissue to store lipids using antioxidant supplementation may prevent the lipotoxic effects and improve the metabolic profile of long-term obesity. Methods: C57BL/6J mice were randomized into three experimental groups for 28 weeks: control group (n510) fed chow diet (10% kcal from fat), obese group (O, n512) fed high-fat (HF) diet (45% kcal from fat), and obese group fed HF diet and supplemented twice a week with 150 mg of a-tocopherol (vitamin E) by oral gavage (OE, n512). Results: HF diet resulted in an obese phenotype with a marked insulin resistance, hypertriglyceridemia, and hepatic steatosis in O mice. Histological analysis of obese visceral adipose tissue (VAT) revealed smaller adipocytes surrounded by a fibrotic extracellular matrix and an increased macrophage infiltration, with the consequent release of proinflammatory cytokines. Vitamin E supplementation decreased oxidative stress and reduced collagen deposition in the VAT of OE mice, allowing a further expansion of the adipocytes and increasing the storage capability. As a result, circulating cytokines were reduced and hepatic steasosis, hypertriglyceridemia, and insulin sensitivity were improved. Conclusions: Our results suggest that oxidative stress is implicated in extracellular matrix remodeling and may play an important role in metabolic regulation.

Los receptores de leptina, una hormona liberada por el tejido adiposo (TA), se expresan por todo el sistema nervioso central. Así mismo, el consumo de dietas ricas en grasas produce un desequilibrio en el TA que conduce a hiperleptinemia, situación capaz de desensibilizar el receptor de leptina (RLep) y conducir a deterioro cognitivo. El objetivo de este trabajo ha sido identificar la influencia de las grasas saturadas (SOLF) y monoinsaturadas (UOLF) en la funcionalidad del RLep en TA, hipotálamo e hipocampo. Para ello, se han alimentado ratones con SOLF/UOLF durante 8 semanas. Nuestros resultados muestran que SOLF y UOLF deterioran la plasticidad sináptica, aunque sólo SOLF produce deterioro de la memoria espacial. Respecto a la señalización del RLep en el hipocampo, SOLF altera la vía de la STAT3, mientras que UOLF desensibiliza las vías de la Akt y la AMPK. En cambio, en el hipotálamo, estas dos vías se bloquean por la dieta SOLF. En el TA, aunque la expresión de leptina solo aumenta con UOLF, SOLF desacopla el RLep de las vías STAT3, Akt y AMPK. En conclusión, nuestro estudio demuestra que la composición de la dieta determina el grado de disfunción hipocampal y de resistencia a leptina.

Hepatectomy and nephrectomy in the rat produced an increase in blood glycerol levels which was observed before the fall in blood glucose. The disappearance of total radioactivity from plasma after the i.v. injection of either (U- 14C)-glycerol or (U- 14C)-glucose in these animals was slower than in their sham operated controls. Total radioactivity in plasma was always lower after (U- 14C)-glycerol administration than after (U- 14C)-glucose. The loss of either tracer from plasma in the eviscerated animals was followed by the appearance of 14C-lactate, demonstrating their rapid metabolism. The radioactivity appearing in the water soluble fraction of lumbar fat pads was increased in eviscerated animals while in the lipid fraction it was reduced from both tracers. These results show that adipose tissue is able to metabolize small quantities of glycerol directly in viva. The use of both (1 4C)-glycerol and (14C)- glucose by skeletal and heart muscles was enhanced in hepatectomized rats but the effect on synthesis of labelled glyceride glycerol was greater for (1 4C)-glycerol, suggesting its important role in the esterification of fatty acids in these tissues.

Plasma-triglyceride levels were higher in pregnant than in virgin rats. The glucose infusion did not modify this parameter, probably because ef the changes in LPL activity in other tissues which are known to occur in the opposite direction to those observed in this study for adipose tissue and mammary gland. The present results support the notion that the insulin resistant condition which normally occurs during late gestation is responsible for the decreased LPL acti11ity in adipose tissue, but that the mammary gland remains sensitive to insulin and so maternal hyperinsulinemia would contribute to the induction of LPL activity in this organ prior to parturition.

Triglyceride-rich lipoproteins (chylomicrons and very low density lipoproteins) were labelled "in vivo" by injecting (U-14C)-glycerol and (9-10(n)-3H)-palmitate in female rats. After purification, these lipoproteins contained most of the 3 H in esterified fatty acids and the 14c in glyceride glycerol of neutral lipids. This preparation was incubated "in vitro" in the presence of either isolated adipocytes or epididymal fat pad pieces from male rats. With the incubation, a certain proportion of both 3 H-esterified fatty acids and 14C-glyceride glycerol disappeared from the medium, the effect being greater when the incubations were performed with adipocytes than with fat pad pieces. Much greater radioactivity appeared in the lipids of adipocytes than in those of fat pad pieces at the end of 60 or 120 min incubation, and the incorporation of 3H being relatively greater than that of 14c. With the latter isotope, the label appeared not only in the glyceride glycerol fraction but also in the free and esterified fatty acids. Although it is known that lipoprotein lipase activity is lower in adipocytes than in fat pad pieces, our results indicate that, in the former preparation, the enzyme may be more accessible for the substrate. These data also demonstrate that glycerol released by the hydrolysis of lipoprotein glycerides may be partially incorporated into lipids by adipose tissue.

During early pregnancy, long-chain polyunsaturated fatty acids (LC-PUFA) may accumulate in maternal fat depots and become available for placental transfer during late pregnancy, when the fetal growth rate is maximal and fetal requirements for LC-PUFAs are greatly enhanced. During this late part of gestation, enhanced lipolytic activity in adipose tissue contributes to the development of maternal hyperlipidaemia; there is an increase in plasma triacylglycerol concentrations, with smaller rises in phospholipid and cholesterol concentrations. Besides the increase in plasma very-low-density lipoprotein, there is a proportional enrichment of triacylglycerols in both low-density lipoproteins and high-density lipoproteins. These lipoproteins transport LC-PUFA in the maternal circulation. The presence of lipoprotein receptors in the placenta allows their placental uptake, where they are hydrolysed by lipoprotein lipase, phospholipase A2 and intracellular lipase. The fatty acids that are released can be metabolized and diffuse into the fetal plasma. Although present in smaller proportions, maternal plasma non-esterified fatty acids are also a source of LC-PU FA for the fetus, their placental transfer being facilitated by the presence of a membrane fatty acid-binding protein. There is very little placental transfer of glycerol, whereas the transfer of ketone bodies may become quantitatively important under conditions of maternal hyperketonaemia, such as during fasting, a high-fat diet or diabetes. The demands for cholesterol in the fetus are high, but whereas maternal cholesterol substantially contributes to fetal cholesterol during early pregnancy, fetal cholesterol biosynthesis rather than cholesterol transfer from maternal lipoproteins seems to be the main mechanism for satisfying fetal requirements during late pregnancy.

In vitro effects of pantethine on adipose tissue lipolysis and on both hepatic and intestinal cholesterol and fatty acid synthesis in normolipidemic rats are determined and related to their respective in vivo hypolipidemic effects after acute oral administration. At 3, 5, 7 and 24 h after a single high dose of pantethine to rats, free fatty acids (FFA), cholesterol and triglycerides levels decreased whereas plasma glycerol increased, the effect becoming significant at 7 h. The release of glycerol and FF A by epididymal fat pad pieces from rats was measured in Krebs Ringer bicarbonate-albumin buffer supplemented or not with epinephrine and several concentrations of pantethine (0, 10 - 5 , 10 -4, or 10 - 3 M), and it turned out to be enhanced as pantethine concentration increased. Besides, when glucose was present in the medium, this drug lowered fatty acid re-esterification in a dose-dependent manner, the effect being specially evident in the presence of epinephrine. In vitro synthesis of both cholesterol and fatty acids by slices of liver or intestinal epithelial cells was depressed as the concentration of pantethine increased in the medium. Thus, an inhibition of both cholesterolgenesis and lipogenesis seems to contribute to the hypocholesterolemic and hypotriglyceridemic effects of pantethine. On the other hand, the stimulation of lipolysis and the inhibition of fatty acid re-esterification on adipose tissue caused by pantethine must be counteracted by a high fatty acid oxidation in the liver which would explain the decrease in FF A and the increase in glycerol levels detected in the plasma of the pantethine-treated animals. © 1998 Elsevier Science B.V. All rights reserved.