Latest approaches for the treatment of obesity

Introduction: Obesity is a body weight disorder characterized by excess adiposity that increases the risk for developing co-morbidities such as type 2 diabetes. A large medical need exists for new anti-obesity treatments capable of promoting 10% or greater weight loss, with minimal side effects.

Areas covered: The authors describe the application of monogenic forms of rare obesity and genome-wide association studies in selecting critical pathways for drug discovery. Furthermore, they review in detail several pathways and pharmacological targets in the central nervous system (e.g., the leptin-melanocortin axis, the opioid system, GLP-1/GLP-1 system, and FGF21/FGFR1c/β-Klotho axis) that play an important role in the regulation of feeding behavior and energy homeostasis. Special focus is given to new strategies that engage well-known targets via novel mechanisms in order to circumvent issues seen with previous drug candidates that failed in the clinic. Finally, the authors discuss the recent developments around fixed-dose combinations, targeted polypharmacology, and non-traditional combinations of drugs and devices.

Expert opinion: The future for new weight-loss approaches to treat obesity looks promising. Current therapies have shown modest effects on weight loss in the general obese population but will have greater impact in smaller homogeneous sub-populations of obese subjects using personalized medicine. Drug combinations that target multiple, complementary pathways have the potential to promote double-digit weight loss in a broader, heterogeneous patient population. Furthermore, the development of advanced subcutaneous delivery technologies has opened up opportunities to develop breakthrough peptide and biologic agents for the treatment of obesity.     

The role of IGF-1 resistance in obesity and type 2 diabetes-mellitus-related insulin resistance and vascular disease

Importance of the field: The insulin-resistant conditions of type 2 diabetes mellitus (T2DM) and obesity are a major cause of cardiovascular disease on a global scale. These disorders are not only a cause of ill health but are a huge financial drain on healthcare systems. T2DM leads to an increased risk of cardiovascular mortality equivalent to over 10 years of ageing while obesity independent of T2DM also leads to a substantially increased risk of acute myocardial infarction. Recent trials of therapeutic agents and approaches to preventing the cardiovascular complications of type 2 diabetes have been disappointing.

Areas covered in this review: The role of insulin resistance in the endothelium in the regulation of the anti-atherosclerotic signalling molecule NO and a potential important role for IGF-1 in vascular NO production.

What the reader will gain: A comprehensive understanding of how insulin and IGF-1 regulate vascular function and the effect of type 2 diabetes on these pathways.

Take home message: The roles of insulin and IGF-1 in vascular function are complex and intimately related. Nevertheless IGF-1 signalling in the arterial wall has the potential to be manipulated to protect the vasculature against the development of atherosclerosis and its devastating complications.     

Novel approaches to drug discovery for the treatment of type 2 diabetes

Introduction: Type 2 diabetes mellitus (T2DM) is a chronic, complex and multifactorial metabolic disorder, which has become a serious global health problem. The side effects of known drugs and the deficiency of long-term safety data, in addition to the already determined adverse effects for the current preclinical drugs against T2DM, have largely called upon the urgent exploration of novel therapeutic and preventative strategies against this disease.

Areas covered: The authors highlight the potential approaches for anti-T2DM drug discovery by focusing on: the restoration of pancreatic β-cell mass, the promotion of insulin secretion, the regulation of oxidative stress and endoplasmic reticulum (ER) stress and the modulation of autophagy.

Expert opinion: T2DM is based on the gradual development of insulin resistance and β-cell dysfunction. Thus, the restoration of β-cell function is considered as one of the promising therapeutic strategies against T2DM. The stress factors, such as oxidative stress, ER stress and autophagy, play potent roles in the regulation of β-cell apoptosis, insulin secretion and sensitivity in the development of T2DM involving complicated cross-talks. Based on multiplex stress-involved regulatory networks, more and more novel potential targets have been discovered and the multi-targeted drug leads are expected to help develop more effective clinical agents for the treatment of T2DM.     

Targeting disease through novel pathways of apoptosis and autophagy

Introduction: Apoptosis and autophagy impact cell death in multiple systems of the body. Development of new therapeutic strategies that target these processes must address their complex role during developmental cell growth as well as during the modulation of toxic cellular environments.

Areas covered: Novel signaling pathways involving Wnt1-inducible signaling pathway protein 1 (WISP1), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), β-catenin and mammalian target of rapamycin (mTOR) govern apoptotic and autophagic pathways during oxidant stress that affect the course of a broad spectrum of disease entities including Alzheimer's disease, Parkinson's disease, myocardial injury, skeletal system trauma, immune system dysfunction and cancer progression. Implications of potential biological and clinical outcome for these signaling pathways are presented.

Expert opinion: The CCN family member WISP1 and its intimate relationship with canonical and non-canonical wingless signaling pathways of PI3K, Akt1, β-catenin and mTOR offer an exciting approach for governing the pathways of apoptosis and autophagy especially in clinical disorders that are currently without effective treatments. Future studies that can elucidate the intricate role of these cytoprotective pathways during apoptosis and autophagy can further the successful translation and development of these cellular targets into robust and safe clinical therapeutic strategies.     

Novel approaches to anti-obesity drug discovery with gut hormones over the past 10 years

ABSTRACT

Introduction: Obesity is a global pandemic and new pharmacotherapies which combine weight loss efficacy, long-term safety, and reversal of metabolic co-morbidities are sorely needed. Gut hormones play key roles in regulating satiety and metabolism, and are natural candidates for therapeutic development.

Areas covered: The authors discuss recent drug developments for the treatment of obesity using gut hormones. The review was based on a search of PubMed using keywords ‘obesity’ AND (‘therapy’ OR ‘pharmacotherapy’ OR ‘gut hormones’ OR ‘analogues’), limited to the last 10 years.

Expert opinion: Analogues of glucagon-like peptide (GLP-1) have been developed for obesity but so far do not provide enough weight loss. Bariatric surgery increases the post-prandial secretion of multiple gut hormones, leading to beneficial effects on weight loss and metabolism. This recognition has led to poly-agonist strategies: GLP-1/glucagon or GLP-1/glucose-dependent insulinotropic peptide (GIP) dual agonism, or even GLP-1/glucagon/GIP triple agonism. New delivery approaches include peptide-conjugate therapies that target key metabolic tissues. Practicable methods for oral delivery of peptide gut hormones are also close to market, expanding the potential market for these treatments. Anti-obesity therapy is therefore poised for an exciting phase, and it will be interesting to see which of these will eventually prevail.     

The therapeutic potential of RNA regulation in neurological disorders

ABSTRACT

Introduction: Gene regulation is the term used to describe the mechanisms by which a cell increases or decreases the amount of a gene product (RNA or protein). In complex organs such as the brain, gene regulation is of the utmost importance; aberrations in the regulation of specific genes can lead to neurological disorders. Understanding these mechanisms can create new strategies for targeting these disorders and progress is being made. Two drugs that function at the RNA level (nusinersen and eteplirsen) have now been approved by the FDA for the treatment of Spinomuscular atrophy and Duchenne muscular dystrophy, respectively; several other compounds for neurological disease are currently being investigated in preclinical studies and clinical trials.

Areas covered: We highlight how gene regulation at the level of RNA molecules can be used as a therapeutic strategy to treat neurological disorders. We provide examples of how such an approach is being studied or used and discuss the current hurdles.

Expert opinion: Targeting gene expression at the RNA level is a promising strategy to treat genetic neurological disorders. Safe administration, long-term efficacy, and potential side effects, however, still need careful evaluation before RNA therapeutics can be applied on a larger scale.     

Antioxidant and α-glucosidase inhibitory activities of Achillea tenorii

Abstract

Context: There is a need for the discovery of novel natural remedies to prevent and treat metabolic disorders such as hyperglycemia, type II non-insulin-dependent diabetes mellitus, and obesity. Several Achillea species have been utilized for centuries all around the world and are generally considered effective as hypoglycemic.

Objective: Considering the ethnobotanical uses of Achillea genus, we evaluated the in vitro inhibitory activity of Achillea tenorii Grande (Asteraceae) extract on α-glucosidase, which is a valuable target to prevent and treat metabolic disorders. We also tested its antioxidant activity. Moreover, the phytochemical profile was discussed from a chemotaxonomic point of view.

Materials and methods: In vitro α-glucosidase inhibition of crude ethanolic extract obtained from the aerial parts was assayed as well as the in vitro antioxidant activity (ABTS, DPPH, and FRAP-FZ tests) was measured. The extract was characterized from a phytochemical point of view by means of spectroscopic analysis.

Results: The extract results endowed with α-glucosidase inhibitory activity (IC₅₀ 32?µg/mL) with a particular mechanism of action definable as un-competitive, which differed from the mechanism observed for the best-known α-glucosidase inhibitor (acarbose and miglitol). In addition, a considerable antioxidant potential has been found for A. tenorii extract, which resulted mainly constituted by phenolic compounds such as caffeoylquinic acids and flavonoids.

Discussion and conclusions: These results suggest the potential of A. tenorii as a possible natural remedy to prevent and treat metabolic disorders of carbohydrates.     

Can targeting SIRT-1 to treat type 2 diabetes be a good strategy? A review

Introduction: Dysregulation of metabolic pathways, caused by imbalances in energy homeostasis, leads to type 2 diabetes characterized by high glucose concentration in the blood due to insulin resistance which is a major disorder in developed countries.

Areas covered: One of the recent treatment strategies is using activators of SIRT1, which has been in clinical trials. Many of the cellular processes including insulin secretion, cell cycle, and apoptosis are imperatively regulated by a family of mediators called sirtuins. First known mammalian sirtuin, SIRT1 is a positive regulator of insulin secretion, which triggers glucose uptake and utilization. Since the past decade, a major outstanding question is whether SIRT1 activation is a safe therapy for human diseases such as type 2 diabetes? This review summarizes and discusses the advances of the past decade and the challenges that will brazen out perplexity about homeostasis and metabolic pathways linked to SIRT1 and type 2 diabetes. Furthermore, we described the interlink between SIRT1 metabolic pathways of various tissues such as pancreas, skeletal muscle, adipose tissue and liver.

Expert opinion: However be the complexity of the pathways involved, T2DM regulated by SIRT1 affected metabolism is dropping down progressively due to profound research. In the context of interlinking all the SIRT1 pathways in T2DM we found various crucial intermediaries in metabolic tissues, which can also be targeted for future prospects.     

Effects of Polygonatum sibiricum rhizome ethanol extract in high-fat diet-fed mice

Abstract

Context: The rhizome of Polygonatum sibiricum Redoute (Liliaceae) has long been used to treat diabetes-associated complications. However, the pharmacological mechanism of P. sibiricum on metabolic disorders is not clear.

Objective: This study investigates the effect of an ethanol extract of P. sibiricum rhizomes (designated ID1216) on obesity conditions including weight loss in high-fat (HF) diet-fed mice and explores the potential underlying mechanisms.

Methods: To identify the metabolic impact of the P. sibiricum rhizome extract, HF diet-fed mice were administered ID1216 orally at doses of 250 and 1000?mg/kg/d for 10?weeks, and various factors related to metabolic syndrome were analyzed. We also examined the effects of ID1216 on the expression of genes involved in adipogenesis and lipolysis in 3T3-L1 cells, as well as genes associated with energy homeostasis in C2C12 myocytes.

Results: ID1216 administration led to significant decreases in body weight gain (37.5%), lipid accumulation in adipose tissues (52.8%), and the levels of plasma triglycerides (26.4%) and free fatty acids (28.1%) at a dose of 250?mg/kg/d, compared with the vehicle-treated group, as well as improved insulin resistance. In addition, ID1216 was found to regulate the expression of genes related to adipogenesis and fatty acid oxidation in 3T3-L1 cells and enhance the expression of genes that modulate energy homeostasis in C2C12 myocytes.

Conclusions: ID1216 may be a promising therapeutic agent for improving obesity conditions through the sirtuin-1 and peroxisome proliferator-activated receptor γ coactivator-1α pathway.     

Anti-inflammatory agents to treat or prevent type 2 diabetes,metabolic syndrome and cardiovascular disease

Introduction: There is a growing body of evidence to suggest that chronic silent inflammation is a key feature in abdominal obesity, metabolic syndrome, type 2 diabetes (T2DM) and cardiovascular disease (CVD). These observations suggest that pharmacological strategies, which reduce inflammation, may be therapeutically useful in treating obesity, type 2 diabetes and associated CVD.

Area covered: The article covers novel strategies, using either small molecules or monoclonal antibodies. These strategies include: approaches targeting IKK-b-NF-kB (salicylates, salsalate), TNF-α (etanercept, infliximab, adalimumab), IL-1β (anakinra, canakinumab) and IL-6 (tocilizumab), AMP-activated protein kinase activators, sirtuin-1 activators, mammalian target of rapamycin inhibitors and C-C motif chemokine receptor 2 antagonists.

Expert opinion: The available data supports the concept that targeting inflammation improves insulin sensitivity and β-cell function; it also ameliorates glucose control in insulin-resistant patients with inflammatory rheumatoid diseases as well in patients with metabolic syndrome or T2DM. Although promising, the observed metabolic effects remain rather modest in most clinical trials. The potential use of combined anti-inflammatory agents targeting both insulin resistance and insulin secretion appears appealing but remains unexplored. Large-scale prospective clinical trials are underway to investigate the safety and efficacy of different anti-inflammatory drugs. Further evidence is needed to support the concept that targeting inflammation pathways may represent a valuable option to tackle the cardiometabolic complications of obesity.     

1H NMR-based metabolic study reveals the improvements of bitter melon (Momordica charantia) on energy metabolism in diet-induced obese mouse

Context: Obesity can be ameliorated by some natural products such as polyphenol, flavones and saponin. As a typical medicinal plant, Momordica charantia L. (Cucurbitaceae) (bitter melon, BM) contains these natural chemicals and reduces diet-induced obesity in mice.

Objective: This study evaluates the metabolic effects of dietary BM supplement, investigates a global metabolic profile and determines associated perturbations in metabolic pathways.

Materials and methods: Male C57BL/6 mice were fed with low-fat diet (LFD), high-fat diet (HFD) and HFD supplemented with 5% BM based on 37.6?g/kg body weight in average for 12 weeks, respectively. Then energy metabolism was quantified using PhenoMaster/LabMaster. The spectroscopy of urine was acquired by nuclear magnetic resonance and latent biomarkers were identified. Pattern recognition analysis was used to discriminate associated metabolic profiles.

Results: Dietary BM supplement reduced body weight gain (?0.15-fold, p?<?0.01) and blood glucose levels (?0.19-fold, p?<?0.01) in HFD-fed mice. Meanwhile, the levels of energy metabolism were enhanced (0.08–0.11-fold, p?<?0.01). According to pattern recognition analysis, dietary BM supplement changed metabolic profiles in HFD-fed mice and the modified profiles were similar to those in LFD-fed mice. Finally, the mapping of metabolic pathways showed that dietary BM supplement primarily affected glucose metabolism-associated pathways.

Discussion and conclusion: The results indicated that BM improves weight loss in diet-induced obesity and elevate energy expenditure in HFD-fed mice. The pattern recognition with metabolic study may be used as a noninvasive detection method to assess the effects of dietary BM supplement on mouse energy metabolism.     

Brain injury with diabetes mellitus: evidence,mechanisms and treatment implications

Introduction: Diabetes mellitus is a risk for brain injury. Brain injury is associated with acute and chronic hyperglycaemia, insulin resistance, hyperinsulinemia, diabetic ketoacidosis (DKA) and hypoglycaemic events in diabetic patients. Hyperglycemia is a cause of cognitive deterioration, low intelligent quotient, neurodegeneration, brain aging, brain atrophy and dementia.

Areas covered: The current review highlights the experimental, clinical, neuroimaging and neuropathological evidence of brain injury induced by diabetes and its associated metabolic derangements. It also highlights the mechanisms of diabetes-induced brain injury. It seems that the pathogenesis of hyperglycemia-induced brain injury is complex and includes combination of vascular disease, oxidative stress, neuroinflammation, mitochondrial dysfunction, apoptosis, reduction of neurotrophic factors, acetylcholinesterase (AChE) activation, neurotransmitters’ changes, impairment of brain repair processes, impairment of brain glymphatic system, accumulation of amyloid β and tau phosphorylation and neurodegeneration. The potentials for prevention and treatment are also discussed.

Expert commentary: We summarize the risks and the possible mechanisms of DM-induced brain injury and recommend strategies for neuroprotection and neurorestoration. Recently, a number of drugs and substances [in addition to insulin and its mimics] have shown promising potentials against diabetes-induced brain injury. These include: antioxidants, neuroinflammation inhibitors, anti-apoptotics, neurotrophic factors, AChE inhibitors, mitochondrial function modifiers and cell based therapies.     

Targeting the 5′-AMP-activated protein kinase and related metabolic pathways for the treatment of prostate cancer

Introduction: Increasing evidence suggests that prostate cancer cells undergo unique metabolic reprogramming during transformation. A master regulator of cellular homeostasis, 5′-AMP-activated protein kinase (AMPK), directs metabolic adaptation that supports the growth demands of rapidly dividing cancer cells. The utilization of AMPK as a therapeutic target may therefore provide an effective strategy in the treatment of prostate cancer.

Areas covered: Our review describes the regulation of AMPK by androgens and upstream kinases including the calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) in prostate cancer. Oncogenic, AMPK-regulated pathways that direct various metabolic processes are also addressed. Furthermore, we discuss the role of AMPK in growth arrest and autophagy as a potential survival pathway for cancer cells. In addition, by regulating non-metabolic pathways, AMPK may stimulate migration and mitosis. Finally, this review summarizes efforts to treat prostate cancer with pharmacological agents capable of modulating AMPK signaling.

Expert opinion: Current research is primarily focused on developing drugs that activate AMPK as a treatment for prostate cancer. However, oncogenic aspects of AMPK signaling calls for caution about employing such therapies. We think that inhibitors of CaMKK2 or AMPK, or perhaps the modulation of downstream targets of AMPK, will gain importance in the clinical management of prostate cancer.     

Non-transfusion-dependent thalassemia and thalassemia intermedia: epidemiology,complications, and management

Objective:

The non-transfusion-dependent thalassemias (NTDTs), including thalassemia intermedia (TI), hemoglobin E beta thalassemia, and hemoglobin H disease, have sometimes been regarded as less severe than their transfusion-dependent variants; however, these disorders carry a substantial disease burden (e.g., splenomegaly, iron overload, skeletal effects, and cardiopulmonary disease). The aim of this review is to increase clinician awareness of the growing global problem of NTDT and TI, and discuss the current management strategies for these conditions.

Methods:

Recent peer-reviewed articles (publication years 2000 through 2015) addressing the epidemiology, complications, management, and monitoring of NTDT were identified in the PubMed database and reviewed.

Results:

The changing epidemiology of thalassemia constitutes a growing health problem. Increased clinician awareness is necessary for the appropriate diagnosis and management of patients with NTDT.

Conclusions:

Management of NTDT requires a comprehensive approach, beginning with screening and prenatal diagnosis, monitoring for iron overload and associated complications, and iron chelation therapy. Several novel strategies are in the early stages of investigation and may help increase treatment options in patients with NTDT. Importantly, ethnic or cultural barriers may exist within the affected populations and need to be considered in the management approach.     

Recent evidence of sustained benefit with exenatide in Type 2 diabetes

Introduction: The incidence of type 2 diabetes mellitus (T2DM) has risen to epidemic proportions, and this is associated with enormous cost. T2DM is preceded by ‘prediabetes’, and the diagnosis of impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) provides an opportunity for targeted intervention. Prediabetic subjects manifest both core defects characteristic of T2DM, that is, insulin resistance and β-cell dysfunction. Interventions which improve insulin sensitivity and/or preserve β-cell function are logical strategies to delay the conversion of IGT/IFG to T2DM or revert glucose tolerance to normal.

Areas covered: The authors examine pharmacologic agents that have proven to decrease the conversion of IGT to T2DM and represent potential treatment options in prediabetes.

Expert opinion: Weight loss improves whole body insulin sensitivity, preserves β-cell function and decreases progression of prediabetes to T2DM. In real life long-term weight loss is the exception and, even if successful, 40 – 50% of IGT individuals still progress to T2DM. Pharmacotherapy provides an alternative strategy to improve insulin sensitivity and preserve β-cell function. Thiazolidinediones (TZDs) are highly effective in T2DM prevention. Long-acting glucagon-like peptide-1 (GLP-1) analogs, because they augment β-cell function and promote weight loss, are effective in preventing IGT progression to T2DM. Metformin is considerably less effective than TZDs or GLP-1 analogs.     

Pharmacotherapeutic management of comorbid polycystic ovary syndrome and diabetes

ABSTRACT

Introduction: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in premenopausal women. Insulin resistance and glucose intolerance are very prevalent metabolic complications in women with PCOS, especially in those presenting with weight excess. Therapeutic strategies targeting insulin resistance in PCOS are of interest because of their overall safety and their beneficial effects on metabolic and reproductive features.

Areas covered: The authors review systematically all of the available therapeutic interventions targeting insulin resistance and/or disturbances of glucose metabolism in women with PCOS.

Expert opinion: The diagnosis of glucose tolerance disorders in women with PCOS requires an oral glucose tolerance test. Strategies addressing weight excess and abdominal adiposity, from lifestyle modification to insulin sensitizers, may improve insulin resistance and glucose tolerance in women with PCOS. However, amelioration of signs and symptoms of PCOS usually requires the loss of large amounts of weight for it to be noticeable. Bariatric surgery has emerged as the most successful approach for obese patients with PCOS, because glucose intolerance, diabetes, and PCOS resolve in most cases through follow-ups. At present, the role of novel drugs targeting insulin resistance and/or diabetes such as inositols, berberine, resveratrol, and incretin-based therapies are yet to be properly established.     

Homeostatic bioenergetic network regulation: a novel concept to avoid pharmacoresistance in epilepsy

Introduction: Despite epilepsy being one of the most prevalent neurological disorders, a third of all patients with epilepsy cannot adequately be treated with available anti-epileptic drugs. One of the significant causes for the failure of conventional pharmacotherapeutic treatment is the development of pharmacoresistance in many forms of epilepsy. The problem of pharmacoresistance has called for the development of new conceptual strategies that improve future drug development efforts.

Areas covered: A thorough review of the recent literature on pharmacoresistance in epilepsy was completed and select examples were chosen to highlight the mechanisms of pharmacoresistance in epilepsy and to demonstrate how those mechanistic findings might lead to improved treatment of pharmacoresistant epilepsy. The reader will gain a thorough understanding of pharmacoresistance in epilepsy and an appreciation of the limitations of conventional drug development strategies.

Expert opinion: Conventional drug development efforts aim to achieve specificity of symptom control by enhancing the selectivity of drugs acting on specific downstream targets; this conceptual strategy bears an undue risk of development of pharmacoresistance. Modulation of homeostatic bioenergetic network regulation is a novel conceptual strategy to affect whole neuronal networks synergistically by mobilizing multiple endogenous biochemical and receptor-dependent molecular pathways. In our expert opinion section, we conclude that homeostatic bioenergetic network regulation might thus be used as an innovative strategy for the control of pharmacoresistant seizures. Recent focal adenosine augmentation strategies support the feasibility of this strategy.     

PPARα as a therapeutic target in inflammation-associated diseases

Introduction: The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) plays a major regulatory function of genes involved in energy metabolism and is a therapeutic target for dyslipidemia. The last decade provided a constellation of findings demonstrating that PPARα behaves as a modulator of both acute and chronic inflammation. PPARα became a rational potential therapeutic target for the treatment of inflammatory disorders.

Aeras covered: The ability of PPARα to control inflammatory signaling pathways via a diversity of molecular mechanisms is discussed. This review is especially focused on the global action of PPARα on inflammation in several tissues from data obtained in numerous cell types and in vivo models exposed to inflammatory stimuli.

Expert opinion: Available PPARα agonists currently used in clinic belong to the class of hypolipidemic drugs but were not expected and not designed to act as anti-inflammatory drugs. To date, accumulating preclinical suggest evidence promising benefits when considering PPARα as a drug target to treat inflammatory disorders. However, clinical studies are needed to validate this concept. Drug design should also be directed toward the elaboration of PPARα agonists more specifically active in the control inflammatory signaling.     

Mitogen-activated protein kinase phosphatase-1 – a potential therapeutic target in metabolic disease

Importance of the field: Metabolic disease, which is associated with obesity and cardiovascular disease, is a worldwide epidemic. There continues to be a tremendous effort towards the development of therapies to curtail obesity and its associated pathophysiological sequelae. MAPKs have been implicated in metabolic disease suggesting that these enzymes, and those that regulate them, can potentially serve as therapeutic targets to combat this disease. The MAPK phosphatase-1 (MKP-1) mediates the dephosphorylation and inactivation of MAPKs in insulin-responsive tissues. Therefore, the actions of MKP-1 may play an important role in the maintenance of metabolic homeostasis.

Areas covered in this review: The functional effects of MKP-1 in MAPK regulation with emphasis on its role in physiological and pathophysiological signaling functions that have been elucidated through the use of mouse genetics.

What the reader will gain: The reader will learn that MAPK inactivation through the effects of MKP-1 is essential for the maintenance of metabolic homeostasis. We will convey the idea that MKP-1 acts as a critical signaling node in MAPK-mediated regulation of cell signaling and metabolism.

Take home message: Pharmacological inactivation of MKP-1 may be of therapeutic value in the treatment of obesity and possibly other metabolic disorders.