Treatment Of Metabolic Diseases Research Articles

The potential function and clinical application of FGF21 in metabolic diseases.

As an endocrine hormone, fibroblast growth factor 21 (FGF21) plays a crucial role in regulating lipid, glucose, and energy metabolism. Endogenous FGF21 is generated by multiple cell types but acts on restricted effector tissues, including the brain, adipose tissue, liver, heart, and skeletal muscle. Intervention with FGF21 in rodents or non-human primates has shown significant pharmacological effects on a range of metabolic dysfunctions, including weight loss and improvement of hyperglycemia, hyperlipidemia, insulin resistance, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Due to the poor pharmacokinetic and biophysical characteristics of native FGF21, long-acting FGF21 analogs and FGF21 receptor agonists have been developed for the treatment of metabolic dysfunction. Clinical trials of several FGF21-based drugs have been performed and shown good safety, tolerance, and efficacy. Here we review the actions of FGF21 and summarize the associated clinical trials in obesity, type 2 diabetes mellitus (T2DM), and NAFLD, to help understand and promote the development of efficient treatment for metabolic diseases via targeting FGF21.

Progress of potential drugs targeted in lipid metabolism research.

Lipids are a class of complex hydrophobic molecules derived from fatty acids that not only form the structural basis of biological membranes but also regulate metabolism and maintain energy balance. The role of lipids in obesity and other metabolic diseases has recently received much attention, making lipid metabolism one of the attractive research areas. Several metabolic diseases are linked to lipid metabolism, including diabetes, obesity, and atherosclerosis. Additionally, lipid metabolism contributes to the rapid growth of cancer cells as abnormal lipid synthesis or uptake enhances the growth of cancer cells. This review introduces the potential drug targets in lipid metabolism and summarizes the important potential drug targets with recent research progress on the corresponding small molecule inhibitor drugs. The significance of this review is to provide a reference for the clinical treatment of metabolic diseases related to lipid metabolism and the treatment of tumors, hoping to deepen the understanding of lipid metabolism and health.

Activating transcription factor 3, glucolipid metabolism, and metabolic diseases.

Lipids and glucose exert many essential physiological functions, such as providing raw materials or energy for cellular biosynthesis, regulating cell signal transduction, and maintaining a constant body temperature. Dysregulation of lipid and glucose metabolism can lead to glucolipid metabolic disorders linked to various metabolic diseases, such as obesity, diabetes, and cardiovascular disease. Therefore, intervention in glucolipid metabolism is a key therapeutic strategy for the treatment of metabolic diseases. Activating transcription factor 3 (ATF3) is a transcription factor that acts as a hub of the cellular adaptive-response network and plays a pivotal role in the regulation of inflammation, apoptosis, DNA repair, and oncogenesis. Emerging evidence has illustrated the vital roles of ATF3 in glucolipid metabolism. ATF3 inhibits intestinal lipid absorption, enhances hepatic triglyceride hydrolysis and fatty acid oxidation, promotes macrophage reverse cholesterol transport, and attenuates the progression of western diet-induced nonalcoholic fatty liver disease and atherosclerosis. In addition to its role in lipid metabolism, ATF3 has also been identified as an important regulator of glucose metabolism. Here, we summarize the recent advances in the understanding of ATF3, mainly focusing on its role in glucose and lipid metabolism and potential therapeutic implications.

Therapeutics in Metabolic Diseases.

Metabolic diseases have important effects on the health and healthcare costs of an individual. It adversely affects various body processes. Metabolic diseases are characterized as the accumulation of many conditions that collectively increase a person's risk of atherosclerotic coronary disease, insulin, and diabetes mellitus intolerance, as well as vascular and neurological complications, such as stroke. Rare metabolic disease has also been reported in literatures and clinical research. Understanding the history and causes of the disease, associated symptoms, disease severity, physical and vital evaluations, etc. is recommended to provide or improve some appropriate therapeutic measure. The experience with patients starts with a critical and general presentation to a healthcare provider that may indicate potential conditions such as dyslipidemia, hypertension, and metabolic diseases. The main factors in the treatment and management of metabolic disorders are lifestyle changes. Whenever behavioral changes are not effective or cannot be implemented, pharmacotherapies should be initiated including for most of the rare diseases. Moreover, pharmaceutical molecules are the very commonly used therapies. The prospect of therapy through gene transfer into somatic cells unlocks a new field of treatment and opportunity for people affected by these genetic conditions. Like other medical treatments, many gene therapies can relieve some, though not every indications of a specific disease, which can increase patients' quality of life. Hormone-based therapies are also implemented in the treatment of metabolic diseases. It has been suggested to use herbal extracts with different forms of nano-drug delivery techniques, such as nanobiocomposites, solid lipid nanoparticles, nanoemulsions, green-synthesized gold, zinc oxide, and silver nanoparticles.

Role of bile acids in overweight and obese children and adolescents.

Bile acids (BAs) are amphipathic molecules synthetized in the liver. They are primarily involved in the digestion of nutrients. Apart from their role in dietary lipid absorption, BAs have progressively emerged as key regulators of systemic metabolism and inflammation. In the last decade, it became evident that BAs are particularly important for the regulation of glucose, lipid, and energy metabolism. Indeed, the interest in role of BA in metabolism homeostasis is further increased due to the global public health increase in obesity and related complications and a large number of research postulating that there is a close mutual relationship between BA and metabolic disorders. This strong relationship seems to derive from the role of BAs as signaling molecules involved in the regulation of a wide spectrum of metabolic pathways. These actions are mediated by different receptors, particularly nuclear farnesoid X receptor (FXR) and Takeda G protein coupled receptor 5 (TGR5), which are probably the major effectors of BA actions. These receptors activate transcriptional networks and signaling cascades controlling the expression and activity of genes involved in BA, lipid and carbohydrate metabolism, energy expenditure, and inflammation. The large correlation between BAs and metabolic disorders offers the possibility that modulation of BAs could be used as a therapeutic approach for the treatment of metabolic diseases, including obesity itself. The aim of this review is to describe the main physiological and metabolic actions of BA, focusing on its signaling pathways, which are important in the regulation of metabolism and might provide new BA -based treatments for metabolic diseases.

ATF5 is a regulator of ER stress and β-cell apoptosis in different mouse models of genetic- and diet-induced obesity and diabetes mellitus

Endoplasmic reticulum (ER) stress is closely associated with type 2 diabetes (T2D). Activating transcription factor 5 (ATF5) is a member of the ATF/cAMP response element binding protein (CREB) family whose levels are increased upon stress in pancreatic islets from mice. Intriguingly, ATF5 deficiency has been shown to contribute to increased ER stress and apoptosis in mouse islet micro-organs. We hypothesized that either deficiency or overexpression of ATF5 is equally deleterious for pancreatic islets in terms of ER stress and apoptosis. To test this, we used a number of in vitro and in vivo models whereby ATF5 levels were overexpressed. We also determined the regulation of ATF5 in the context of metabolic derangements by using various mouse models of obesity and T2D. Our in vitro results show that ATF5 overexpression promoted palmitic acid (PA)-induced lipotoxic apoptosis. In vivo, global ATF5 overexpression in mice was lethal and pancreas-specific ATF5 overexpressing mice exhibit increased β-cell apoptosis. Interestingly, ATF5 is downregulated in all mouse models of severe obesity and T2D used in the current study. In conclusion, a tight control on ATF5 levels might be considered when developing novel agents targeting ATF5 for prevention and treatment of metabolic diseases.

The effects of dual GLP-1/GCG receptor agonists with different receptor selectivity in mouse models of obesity and NASH.

There is an unmet need for NASH therapeutics, considering the increase in global obesity. Dual GLP-1/GCG receptor agonists have shown beneficial effects in circumventing the pathophysiology linked to NASH. However, dual GLP-1/GCG receptor agonists as a treatment for metabolic diseases need delicate optimisation to maximise metabolism effects. The impacts of increased relative GLP-1/GCG receptor activity in NASH settings must be addressed to unleash the full potential. In this study, we investigated the potential of OXM-104 and OXM-101, two dual GLP-1/GCG receptor agonists with different selectivity in the setting of NASH, to establish the relative receptor activities leading to the best metabolic outcome efficacies to reduce the gap between surgery and pharmacological interventions. We developed dual GLP-1/GCG receptor agonists with selective agonism. Despite the improved metabolic effects of OXM-101, we explored a hyperglycemic risk attached to increased relative GCG receptor agonism. Thirty-eight days of treatment with a dual GLP-1/GCG receptor agonist OXM-104 with increased GLP-1 receptor agonism in obese NASH mice was found to ameliorate the development of NASH by lowering body weight, improving liver and lipid-profiles, reducing levels of the fibrosis marker PRO-C4, and improve glucose control. Similarly, dual GLP-1/GCG receptor agonist OXM-101 with increased relative GCG receptor agonism ameliorated NASH by eliciting dramatic bodyweight reductions to OXM-104, reflected in the improvement of liver and lipid enzymes and reduced PRO-C4 levels. Optimising GLP-1/GCG agonists with increased relative GCG receptor agonism can provide the setting for future agonists to treat obesity, type 2 diabetes, and NASH without having a hyperglycemic risk. Significance Statement There is an unmet need for NASH therapeutics considering the increase in global obesity. Dual GLP-1/GCG receptor agonists have shown beneficial effects in circumventing the pathophysiology linked to NASH. Therefore, we have examined OXM-104 and OXM-101, two dual GLP-1/GCG receptor agonists in the setting of NASH, to establish the relative receptor activities leading to the best metabolic outcome efficacies to reduce the gap between surgery and pharmacological interventions.

Advances in T Cells Based on Inflammation in Metabolic Diseases.

With the increasing incidence of metabolic diseases year by year and their impact on the incidence of cardiovascular diseases, metabolic diseases have attracted great attention as a major health care problem, but there is still no effective treatment. Oxidative stress and inflammation are the main mechanisms leading to metabolic diseases. T cells are involved in the inflammatory response, which can also regulate the development of metabolic diseases, CD4+ T cells and CD8+ T cells are mainly responsible for the role. Th1 and Th17 differentiated from CD4+ T promote inflammation, while Th2 and Treg inhibit inflammation. CD8+ T cells also contribute to inflammation. The severity and duration of inflammatory reactions can also lead to different degrees of progression of metabolic diseases. Moreover, mTOR, PI3K-Akt, and AMPK signaling pathways play unique roles in the regulation of T cells, which provide a new direction for the treatment of metabolic diseases in the future. In this review, we will elaborate on the role of T cells in regulating inflammation in various metabolic diseases, the signaling pathways that regulate T cells in metabolic diseases, and the latest research progress.

Resveratrol impacts health in patients with diabetes mellitus and other metabolic conditions

Background Resveratrol is a polyphenol with many properties, including activity against glycation, oxidative stress, inflammation, neurodegeneration, carcinogenesis and aging. It appears to be a promising compound for the prevention and treatment of metabolic diseases. The aim of this review is to summarize the results of the latest clinical trials that concern effects of resveratrol in diabetes mellitus type 1 and 2 and its complications - diabetic foot ulcers, diabetic nephropathy and non-alcoholic fatty liver disease. Aim of the study Based on in vitro studies and animal models, it has been observed that resveratrol reverses the factors causing premature death: obesity, hypertension, and hyperlipidemia. Because of its anti-inflammatory, antioxidant, cardioprotective and blood lowering glucose effects, it appears to be a promising compound for the treatment of metabolic conditions. The review presents different clinical trials concerning the efficiency of resveratrol supplementation in patients with diabetes mellitus and metabolic syndrome and their complications. Most studies focused on assessing the effect of resveratrol supplementation as an adjunctive treatment of diabetes mellitus type 2 and in this group of patients it gave the best results causing reduction of fasting glucose levels, fasting insulin concentration, insulin resistance and improvement of insulin sensitivity and lipid profiles. Conclusions Resveratrol remains a potential drug in the treatment of metabolic diseases like diabetes mellitus. However, the results of the conducted trials are inconscient. More research is needed to confirm the effectiveness of resveratrol supplementation in treating diabetes, its complications and other metabolic conditions.

Curcumin improves insulin sensitivity in high-fat diet-fed mice through gut microbiota

BackgroundInsulin resistance precedes metabolic syndrome which increases the risk of type 2 diabetes and cardiovascular disease. However, there is a lack of safe and long-lasting methods for the prevention and treatment of insulin resistance. Gut microbiota dysbiosis can lead to insulin resistance and associated glucose and lipid metabolic dysfunction. Thus, the role of gut microbiota in metabolic diseases has garnered growing interest. Curcumin, the active ingredient of tropical plant Curcuma longa, has excellent prospects for the prevention and treatment of metabolic diseases. However, due to the extremely low bioavailability of curcumin, the mechanisms by which curcumin increases insulin sensitivity remains to be elucidated. This study aimed to elucidate the role of gut microbiota in mediating the effects of curcumin on improving insulin sensitivity in high-fat diet (HFD)-fed mice.MethodsGlucose, insulin, and pyruvate tolerance were tested and hepatic triglycerides (TGs) content was measured in HFD-fed mice treated with curcumin (100 mg kg−1 d−1, p.o.) or vehicle for 4 weeks and aforementioned mice after gut microbiota depletion via antibiotic treatment for 4 weeks. Fecal microbiota transplantation (FMT) was conducted in endogenous gut microbiota-depleted HFD-fed mice. Glucose and lipid metabolic phenotypes were also measured in recipient mice colonized microbiota from vehicle- or curcumin-treated HFD-fed mice. The mechanisms underlying the effects of curcumin on increasing insulin sensitivity were testified by Western blotting, real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA).ResultsCurcumin ameliorated HFD-induced glucose intolerance, insulin resistance, pyruvate intolerance, and hepatic TGs accumulation, while these effects were mediated by gut microbiota. Curcumin induced insulin-stimulated Akt phosphorylation levels in insulin-regulated peripheral tissues. The inhibitory effects of curcumin on the expressions of genes involved in hepatic gluconeogenesis and de novo lipogenesis were dependent on gut microbiota. Meanwhile, curcumin upregulated the expression of fibroblast growth factor 15 (FGF15) through gut microbiota.ConclusionsThe effects of curcumin on promoting insulin sensitivity were dependent on gut microbiota in HFD-fed mice. Moreover, curcumin at least partly exerted its effects on increasing insulin sensitivity via FGF15 upregulation. This study provided new ideas on nutritional manipulations of gut microbiota for the treatment of metabolic diseases.

Detection of brown adipose tissue in rats with acute cold stimulation using quantitative susceptibility mapping.

Detection of brown adipose tissue in rats with acute cold stimulation using quantitative susceptibility mapping.

Acute changes in systemic glycemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis.

Therapies based on glucagon-like peptide-1 (GLP-1) long-acting analogs and insulin are often used in the treatment of metabolic diseases. Both insulin and GLP-1 receptors are expressed in metabolically relevant brain regions, suggesting a cooperative action. However, the mechanisms underlying the synergistic actions of insulin and GLP-1R agonists remain elusive. In this study, we show that insulin-induced hypoglycemia enhances GLP-1R agonists entry in hypothalamic and area, leading to enhanced whole-body fat oxidation. Mechanistically, this phenomenon relies on the release of tanycyctic vascular endothelial growth factor A, which is selectively impaired after calorie-rich diet exposure. In humans, low blood glucose also correlates with enhanced blood-to-brain passage of insulin, suggesting that blood glucose gates the passage other energy-related signals in the brain. This study implies that the preventing hyperglycemia is important to harnessing the full benefit of GLP-1R agonist entry in the brain and action onto lipid mobilization and body weight loss.

PSuc-EDBAM: Predicting lysine succinylation sites in proteins based on ensemble dense blocks and an attention module

BackgroundLysine succinylation is a newly discovered protein post-translational modifications. Predicting succinylation sites helps investigate the metabolic disease treatments. However, the biological experimental approaches are costly and inefficient, it is necessary to develop efficient computational approaches.ResultsIn this paper, we proposed a novel predictor based on ensemble dense blocks and an attention module, called as pSuc-EDBAM, which adopted one hot encoding to derive the feature maps of protein sequences, and generated the low-level feature maps through 1-D CNN. Afterward, the ensemble dense blocks were used to capture feature information at different levels in the process of feature learning. We also introduced an attention module to evaluate the importance degrees of different features. The experimental results show that Acc reaches 74.25%, and MCC reaches 0.2927 on the testing dataset, which suggest that the pSuc-EDBAM outperforms the existing predictors.ConclusionsThe experimental results of ten-fold cross-validation on the training dataset and independent test on the testing dataset showed that pSuc-EDBAM outperforms the existing succinylation site predictors and can predict potential succinylation sites effectively. The pSuc-EDBAM is feasible and obtains the credible predictive results, which may also provide valuable references for other related research. To make the convenience of the experimental scientists, a user-friendly web server has been established (http://bioinfo.wugenqiang.top/pSuc-EDBAM/), by which the desired results can be easily obtained.

The Therapeutic Potential of Plant Polysaccharides in Metabolic Diseases.

Plant polysaccharides (PPS) composed of more than 10 monosaccharides show high safety and various pharmacological activities, including immunoregulatory, antitumor, antioxidative, antiaging, and other effects. In recent years, emerging evidence has indicated that many PPS are beneficial for metabolic diseases, such as cardiovascular disease (CVD), diabetes, obesity, and neurological diseases, which are usually caused by the metabolic disorder of fat, sugar, and protein. In this review, we introduce the common characteristics and functional activity of many representative PPS, emphasize the common risks and molecular mechanism of metabolic diseases, and discuss the pharmacological activity and mechanism of action of representative PPS obtained from plants including Aloe vera, Angelica sinensis, pumpkin, Lycium barbarum, Ginseng, Schisandra chinensis, Dioscorea pposite, Poria cocos, and tea in metabolic diseases. Finally, this review will provide directions and a reference for future research and for the development of PPS into potential drugs for the treatment of metabolic diseases.

Protective effect of traditional Chinese medicine on non-alcoholic fatty liver disease and liver cancer by targeting ferroptosis.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease with high incidence and is closely related to metabolic syndrome. If not controlled, it may eventually become hepatocellular carcinoma (HCC). Ferroptosis, a non-apoptotic form of programmed cell death (PCD), is closely related to NAFLD and HCC, and the mechanisms of action involved are more complex. Some studies have demonstrated that many drugs inhibit ferroptosis and protect liver steatosis or carcinogenesis. The role of Traditional Chinese Medicine (TCM), especially herbs or herbal extracts, has received increasing attention. However, there are relatively few review articles on the regulation of NAFLD by TCM through ferroptosis pathway. Here, we summarize the TCM intervention mechanism and application affecting NAFLD/NAFLD-HCC via regulation of ferroptosis. This article focuses on the relationship between ferroptosis and NAFLD or NAFLD-HCC and the protective effect of TCM on both by targeting ferroptosis. It not only summarizes the mechanism of early prevention and treatment of NAFLD, but also provides reference ideas for the development of TCM for the treatment of metabolic diseases and liver diseases.

Fibroblast growth factor 21 and dietary macronutrient intake in female mice

Fibroblast growth factor- 21 (FGF21) is a metabolic stress hormone that is released from the liver in response to various nutritional challenges. Because of its notable effects to improve metabolic health, including body fat loss, glucose control, and hepatosteatosis, several pharmaceutical analogs of FGF21 are in development for the treatment of metabolic disease. In addition, a small but developing literature clearly demonstrates that FGF21 also controls feeding behavior. Pharmacological administration of FGF21 reduces the consumption of simple sugars and other sweet tastants, and it increases the consumption of dietary proteins in males, suggesting another potential mechanism by which FGF21-treatment could improve metabolic health— by promoting healthy eating. Despite that sex is a key biological variable influencing feeding behavior and macronutrient selection, the current literature to date primarily on males. In this study, we investigated the effect of FGF21 on sucrose intake and macronutrient selection in female mice. Similar to our previous findings in male mice, we report that FGF21 administration decreases the consumption of sucrose solution by females, and that this is offset by increased chow intake. Also in agreement with our previous findings in males, we report that FGF21 increases the consumption of dietary protein by female mice, and this is offset by either reduced carbohydrate or by reduced fat intake. Lastly, we find that the effect of FGF21 to direct macronutrient intake in females depends on its actions in neurons. Overall, our data support a role for FGF21 to direct macronutrient intake in a similar manner in female and male mice.

FGF21 controls hepatic lipid metabolism via sex-dependent interorgan crosstalk.

The liver regulates energy partitioning and use in a sex-dependent manner, coupling hepatic substrate availability to female reproductive status. Fibroblast growth factor 21 (FGF21) is a hepatokine produced in response to metabolic stress that adaptively directs systemic metabolism and substrate use to reduce hepatic lipid storage. Here we report that FGF21 altered hepatic transcriptional and metabolic responses, and reduced liver triglycerides, in a sex-dependent manner. FGF21 decreased hepatic triglycerides in obese male mice in a weight loss-independent manner; this was abrogated among female littermates. The effect of FGF21 on hepatosteatosis is thought to derive, in part, from increased adiponectin secretion. Accordingly, plasma adiponectin and its upstream adrenergic receptor → cAMP → exchange protein directly activated by cAMP signaling pathway was stimulated by FGF21 in males and inhibited in females. Both ovariectomized and reproductively senescent old females responded to FGF21 treatment by decreasing body weight, but liver triglycerides and adiponectin remained unchanged. Thus, the benefit of FGF21 treatment for improving hepatosteatosis depends on sex but not on a functional female reproductive system. Because FGF21 provides a downstream mechanism contributing to several metabolic interventions, and given its direct clinical importance, these findings may have broad implications for the targeted application of nutritional and pharmacological treatments for metabolic disease.

Gypenosides counteract hepatic steatosis and intestinal barrier injury in rats with metabolic associated fatty liver disease by modulating the adenosine monophosphate activated protein kinase and Toll-like receptor 4/nuclear factor kappa B pathways

Context Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease, can develop into metabolic associated fatty liver disease (MAFLD). Gypenosides (GP), the main phytochemical component of Gynostemma pentaphylla (Thunb.) Makino (Cucurbitaceae), have been applied for treatment of metabolic diseases. Objective We investigate how GP modulate MAFLD-related hepatic steatosis and intestinal barrier injury. Materials and methods In cell experiments, Caco-2 cells were treated with GP (150 or 200 μmol/L, 24 h), following lipopolysaccharide (LPS) exposure (10 μg/mL, 24 h) to mimic MAFLD in vitro. In in vivo experiments, control, model and model + GP groups were set. High fructose diet/high fat (HFD/HF)-fed (12 weeks) MAFLD rats received GP treatment (300 mg/kg, 6 weeks), followed by intra-peritoneal glucose tolerance test and histopathological examination of rat liver and intestinal mucosa using haematoxylin–eosin staining. Results GP at 200 μM significantly reversed LPS-induced decreases in transepithelial electrical resistance (TER) value (25%), protein expression of occludin (two fold) and ZO-1 (four fold), and the ratio of p-AMPK to AMPK (five fold), while partially repressing LPS-induced leakage of FD4 (50%) and LPS-induced increases in the Toll-like receptor 4 (TLR4) level (50%) and the ratio of p-p65 to p65 (55%). Compared with the model rats, rats with GP treatment presented a reduction in gain of weight and glucose tolerance. In addition, GP alleviated HFD/HF-induced histopathological abnormalities in rat liver and intestinal mucosa. Conclusions GP attenuates hepatic steatosis and intestinal barrier injury in MAFLD rats via the AMPK and TLR4/nuclear factor kappa B (NF-κB) pathways, providing a potential treatment for MAFLD patients.

Gastric bypass surgery weight loss-independently induces gut Il-22 release in association with improved glycemic control in obese Zucker fatty rats

BackgroundRoux-en-Y gastric bypass surgery (RYGB) improves glycemic control in individuals with severe obesity beyond the effects of weight loss alone. To identify potential underlying mechanisms, we asked how equivalent weight loss from RYGB and from chronic caloric restriction impact gut release of the metabolically beneficial cytokine interleukin-22 (Il-22). MethodsObese male Zucker fatty rats were randomized into sham-operated (Sham), RYGB, and sham-operated, body weight-matched to RYGB (BWM) groups. Food intake and body weight were measured regularly for 4 weeks. An oral glucose tolerance test (OGTT) was performed on postoperative day 27. Portal vein plasma, systemic plasma, and whole-wall samples from throughout the gut were collected on postoperative day 28. Gut Il-22 mRNA expression was determined by real-time quantitative PCR. Plasma Il-22 levels were determined by enzyme-linked immunosorbant assay (ELISA). ResultsRYGB and BWM rats had lower food intake and body weight as well as superior blood glucose clearing capability compared with Sham rats. RYGB rats also had superior blood glucose clearing capability compared with BWM rats despite having similar body weights and higher food intake. Il-22 mRNA expression was approximately 100-fold higher specifically in the upper jejunum in RYGB rats compared with Sham rats. Il-22 protein was only detectable in portal vein (34.1 ± 9.4 pg/mL) and systemic (46.9 ± 10.5 pg/mL) plasma in RYGB rats. Area under the curve of blood glucose during the OGTT, but not food intake or body weight, negatively correlated with portal vein and systemic plasma Il-22 levels in RYGB rats. ConclusionsThese results suggest that induction of gut Il-22 release might partly account for the weight loss-independent improvements in glycemic control after RYGB, and further support the use of this cytokine for the treatment of metabolic disease.

The beneficial metabolic actions of prolactin.

The role of prolactin (PRL) favoring metabolic homeostasis is supported by multiple preclinical and clinical studies. PRL levels are key to explaining the direction of its actions. In contrast with the negative outcomes associated with very high (>100 μg/L) and very low (<7 μg/L) PRL levels, moderately high PRL levels, both within but also above the classically considered physiological range are beneficial for metabolism and have been defined as HomeoFIT-PRL. In animal models, HomeoFIT-PRL levels counteract insulin resistance, glucose intolerance, adipose tissue hypertrophy and fatty liver; and in humans associate with reduced prevalence of insulin resistance, fatty liver, glucose intolerance, metabolic syndrome, reduced adipocyte hypertrophy, and protection from type 2 diabetes development. The beneficial actions of PRL can be explained by its positive effects on main metabolic organs including the pancreas, liver, adipose tissue, and hypothalamus. Here, we briefly review work supporting PRL as a promoter of metabolic homeostasis in rodents and humans, the PRL levels associated with metabolic protection, and the proposed mechanisms involved. Finally, we discuss the possibility of using drugs elevating PRL for the treatment of metabolic diseases.