Hypothalamic Control Of Energy Balance Research Articles

Regulation of Leptin Receptor Signaling by Gangliosides

Gangliosides are glycosphingolipids containing one or more sialic acids, and abundantly exist in the central nervous system. They are fundamental components of cell membrane microdomains and interact laterally with membrane proteins, thereby regulating functions of transmembrane receptors such as epidermal growth factor receptor and insulin receptor. Studies using genetically engineered mice and neuronal cells for glycosyltransferase genes involved in glycosphingolipid synthesis provide insights into the roles of gangliosides in hypothalamic control of energy balance through leptin receptor signaling. This minireview summarizes current understanding of the mechanisms and discusses how ganglioside species regulate leptin receptor signaling.

Roles of Gangliosides in Hypothalamic Control of Energy Balance: New Insights.

Gangliosides are essential components of cell membranes and are involved in a variety of physiological processes, including cell growth, differentiation, and receptor-mediated signal transduction. They regulate functions of proteins in membrane microdomains, notably receptor tyrosine kinases such as insulin receptor (InsR) and epidermal growth factor receptor (EGFR), through lateral association. Studies during the past two decades using knockout (KO) or pharmacologically inhibited cells, or KO mouse models for glucosylceramide synthase (GCS; Ugcg), GM3 synthase (GM3S; St3gal5), and GD3 synthase (GD3S; St8sia1) have revealed essential roles of gangliosides in hypothalamic control of energy balance. The a-series gangliosides GM1 and GD1a interact with leptin receptor (LepR) and promote LepR signaling through activation of the JAK2/STAT3 pathway. Studies of GM3S KO cells have shown that the extracellular signal-regulated kinase (ERK) pathway, downstream of the LepR signaling pathway, is also modulated by gangliosides. Recent studies have revealed crosstalk between the LepR signaling pathway and other receptor signaling pathways (e.g., InsR and EGFR pathways). Gangliosides thus have the ability to modulate the effects of leptin by regulating functions of such receptors, and by direct interaction with LepR to control signaling.

The Role of Dietary Advanced Glycation End Products in Metabolic Dysfunction.

Advanced glycation end products (AGEs) are a heterogeneous group of molecules produced, non-enzymatically, from the interaction between reducing sugars and the free amino groups of proteins, nucleic acids, and lipids. AGEs are formed as a normal consequence of metabolism but can also be absorbed from the diet. They have been widely implicated in the complications of diabetes affecting cardiovascular health, the nervous system, eyes, and kidneys. Increased levels of AGEs are also detrimental to metabolic health and may contribute to the metabolic abnormalities induced by the Western diet, which is high in processed foods and represents a significant source of AGEs. While increased AGE levels are a consequence of diabetic hyperglycaemia, AGEs themselves activate signaling pathways, which compromise insulin signaling and pancreatic β-cell function, thus, contributing to the development of type 2 diabetes mellitus (T2DM). Furthermore, AGEs may also contribute to the obesogenic effects of the Western diet by promoting hypothalamic inflammation and disrupting the central control of energy balance. Here, the role of dietary AGEs in metabolic dysfunction is reviewed with a focus on the mechanisms underpinning their detrimental role in insulin resistance, pancreatic β-cell dysfunction, hypothalamic control of energy balance, and the pathogenesis of T2DM and obesity.

Bisphenol A Alters Bmal1, Per2, and Rev-Erba mRNA and Requires Bmal1 to Increase Neuropeptide Y Expression in Hypothalamic Neurons.

Bisphenol A (BPA), a ubiquitous environmental endocrine disruptor, is considered an obesogen. However, its role in the hypothalamic control of energy balance remains largely unexplored. Because disruption of the circadian clock is tightly associated with metabolic consequences, we explored how BPA affects the components of the molecular circadian clock in the feeding-related neurons of the hypothalamus. In immortalized POMC and NPY/AgRP-expressing hypothalamic cell lines and primary culture, we describe how BPA significantly alters mRNA expression of circadian clock genes Bmal1,Per2, and Rev-Erbα. Furthermore, we use newly generated Bmal1-knockout (KO) hypothalamic cell lines to link the BPA-induced neuropeptide dysregulation to the molecular clock. Specifically, BPA increased Npy, Agrp, and Pomc mRNA expression in wild type hypothalamic cells, whereas the increase in Npy, but not Agrp or Pomc, was abolished in cell lines lacking BMAL1. In line with this increase, BPA led to increased BMAL1 binding to the Npy promotor, potentially increasing Npy transcription. In conclusion, we show that BPA-mediated dysregulation of the circadian molecular clock is linked to the deleterious effects of BPA on neuropeptide expression. Furthermore, we describe hypothalamic Bmal1-KO cell lines to study the role of BMAL1 in hypothalamic responses to metabolic, hormonal, and environmental factors.

Neuropeptide Y Leu7Pro polymorphism is not associated with risk of developing obesity in Pakistani population

Background/objectivesThe role of Neuropeptide Y in the hypothalamic control of energy balance is well established. NPY is a well-known, orexigenic peptide. Apart from increasing food intake and reducing state of satiety, NPY stimulates fat angiogenesis, proliferation and differentiation of new adipocytes, resulting in development of abdominal obesity and metabolic syndrome-like conditions. Although there is extensive evidence of the key role of NPY in energy regulation in pre-clinical studies, evidence in humans is limited. However, single nucleotide polymorphism in the signal peptide of NPY Leu7Pro, which causes an amino acid change from leucine to proline, has been found to increase susceptibility to obesity in various populations. Therefore, we sought to genotype screen NPY Leu7Pro allele in overweight, obese and normal Pakistani individuals. MethodA total of 364 randomly selected participants were genotyped screen for the NPY Leu7Pro using PCR-RFLP followed by Sanger sequencing for conformation of the results. The participants were divided into normal, overweight and obese categories based on the BMI. ResultsOf the 364 samples screened, only one sample showed the heterozygous TC genotype. All the other samples showed homozygous TT (normal) genotype. No CC genotype was observed in both the overweight, obese and control groups. ConclusionThe NPY SNP Leu7Pro is found to be extremely rare in Pakistani population and does not contribute towards risk of developing obesity.

Lateral Hypothalamic Control of Energy Balance

Abstract Food and water are necessary for survival, but can only be obtained via ingestive behaviors (feeding, drinking, and moving). Survival thus depends on the ability of the brain to coordinate...

Bifidobacterium pseudocatenulatum CECT 7765 Ameliorates Neuroendocrine Alterations Associated with an Exaggerated Stress Response and Anhedonia in Obese Mice.

Obesity, besides being a problem of metabolic dysfunction, constitutes a risk factor for psychological disorders. Experimental models of diet-induced obesity have revealed that obese animals are prone to anxious and depressive-like behaviors. The present study aimed to evaluate whether Bifidobacterium pseudocatenulatum CECT 7765 could reverse the neurobehavioral consequences of obesity in a high-fat diet (HFD) fed mouse model via regulation of the gut-brain axis. Adult male wild-type C57BL-6 mice were fed a standard diet or HFD, supplemented with either placebo or the bifidobacterial strain for 13 weeks. Behavioral tests were performed, and immune and neuroendocrine parameters were analyzed including leptin and corticosterone and their receptors, Toll-like receptor 2 (TLR2) and neurotransmitters. We found that obese mice showed anhedonia (p<0.050) indicative of a depressive-like behavior and an exaggerated hypothalamic-pituitary axis (HPA)-mediated stress response to acute physical (p<0.001) and social stress (p<0.050), but these alterations were ameliorated by B. pseudocatenulatum CECT 7765 (p<0.050). These behavioral effects were parallel to reductions of the obesity-associated hyperleptinemia (p<0.001) and restoration of leptin signaling (p<0.050), along with fat mass loss (p<0.010). B. pseudocatenulatum CECT 7765 administration also led to restoration of the obesity-induced reductions in adrenaline in the hypothalamus (p<0.010), involved in the hypothalamic control of energy balance. Furthermore, the bifidobacterial strain reduced the obesity-induced upregulation of TLR2 protein or gene expression in the intestine (p<0.010) and the hippocampus (p<0.050) and restored the alterations of 5-HT levels in the hippocampus (p<0.050), which could contribute to attenuating the obesity-associated depressive-like behavior (p<0.050). In summary, the results indicate that B. pseudocatenulatum CECT 7765 could play a role in depressive behavior comorbid with obesity via regulation of endocrine and immune mediators of the gut-brain axis.

Hypothalamic Inflammation and Energy Balance Disruptions: Spotlight on Chemokines.

The hypothalamus is a key brain region in the regulation of energy balance as it controls food intake and both energy storage and expenditure through integration of humoral, neural, and nutrient-related signals and cues. Many years of research have focused on the regulation of energy balance by hypothalamic neurons, but the most recent findings suggest that neurons and glial cells, such as microglia and astrocytes, in the hypothalamus actually orchestrate together several metabolic functions. Because glial cells have been described as mediators of inflammatory processes in the brain, the existence of a causal link between hypothalamic inflammation and the deregulations of feeding behavior, leading to involuntary weight loss or obesity for example, has been suggested. Several inflammatory pathways that could impair the hypothalamic control of energy balance have been studied over the years such as, among others, toll-like receptors and canonical cytokines. Yet, less studied so far, chemokines also represent interesting candidates that could link the aforementioned pathways and the activity of hypothalamic neurons. Indeed, chemokines, in addition to their role in attracting immune cells to the inflamed site, have been suggested to be capable of neuromodulation. Thus, they could disrupt cellular activity together with synthesis and/or secretion of multiple neurotransmitters/mediators involved in the maintenance of energy balance. This review discusses the different inflammatory pathways that have been identified so far in the hypothalamus in the context of feeding behavior and body weight control impairments, with a particular focus on chemokines signaling that opens a new avenue in the understanding of the major role played by inflammation in obesity.

Perturbation of Hypothalamic MicroRNA Expression Patterns in Male Rats After Metabolic Distress: Impact of Obesity and Conditions of Negative Energy Balance

The hypothalamus plays a crucial role in body weight homeostasis through an intricate network of neuronal circuits that are under the precise regulation of peripheral hormones and central transmitters. Although deregulated function of such circuits might be a major contributing factor in obesity, the molecular mechanisms responsible for the hypothalamic control of energy balance remain partially unknown. MicroRNAs (miRNAs) have been recognized as key regulators of different biological processes, including insulin sensitivity and glucose metabolism. However, the roles of miRNA pathways in the control of metabolism have been mostly addressed in peripheral tissues, whereas the potential deregulation of miRNA expression in the hypothalamus in conditions of metabolic distress remains as yet unexplored. In this work, we used high-throughput screening to define to what extent the hypothalamic profiles of miRNA expression are perturbed in two extreme conditions of nutritional stress in male rats, namely chronic caloric restriction and high-fat diet-induced obesity. Our analyses allowed the identification of sets of miRNAs, including let-7a, mir-9*, mir-30e, mir-132, mir-145, mir-200a, and mir-218, whose expression patterns in the hypothalamus were jointly altered by caloric restriction and/or a high-fat diet. The predicted targets of these miRNAs include several elements of key inflammatory and metabolic pathways, including insulin and leptin. Our study is the first to disclose the impact of nutritional challenges on the hypothalamic miRNA expression profiles. These data will help to characterize the molecular miRNA signature of the hypothalamus in extreme metabolic conditions and pave the way for targeted mechanistic analyses of the involvement of deregulated central miRNAs pathways in the pathogenesis of obesity and related disorders.

Hypothalamic dysfunction in obesity

A growing number of studies have shown that a diet high in long chain SFA and/or obesity cause profound changes to the energy balance centres of the hypothalamus which results in the loss of central leptin and insulin sensitivity. Insensitivity to these important anorexigenic messengers of nutritional status perpetuates the development of both obesity and peripheral insulin insensitivity. A high-fat diet induces changes in the hypothalamus that include an increase in markers of oxidative stress, inflammation, endoplasmic reticulum (ER) stress, autophagy defect and changes in the rate of apoptosis and neuronal regeneration. In addition, a number of mechanisms have recently come to light that are important in the hypothalamic control of energy balance, which could play a role in perpetuating the effect of a high-fat diet on hypothalamic dysfunction. These include: reactive oxygen species as an important second messenger, lipid metabolism, autophagy and neuronal and synaptic plasticity. The importance of nutritional activation of the Toll-like receptor 4 and the inhibitor of NF-κB kinase subunit β/NK-κB and c-Jun amino-terminal kinase 1 inflammatory pathways in linking a high-fat diet to obesity and insulin insensitivity via the hypothalamus is now widely recognised. All of the hypothalamic changes induced by a high-fat diet appear to be causally linked and inhibitors of inflammation, ER stress and autophagy defect can prevent or reverse the development of obesity pointing to potential drug targets in the prevention of obesity and metabolic dysfunction.

Defective Hypothalamic Autophagy Directs the Central Pathogenesis of Obesity via the IκB Kinase β (IKKβ)/NF-κB Pathway

Autophagy has been recently demonstrated to control cell and tissue homeostasis, including the functions of various metabolic tissues. However, it remains unclear whether autophagy is critical for the central nervous system and particularly the hypothalamus for exerting metabolic regulation. Using autophagy-related protein 7 (Atg7) as an autophagic marker, this work showed that autophagy was highly active in the mediobasal hypothalamus of normal mice. In contrast, chronic development of dietary obesity was associated with autophagic decline in the mediobasal hypothalamus. To investigate the potential role of autophagy in the hypothalamic control of metabolic physiology, a mouse model was developed with autophagic inhibition in the mediobasal hypothalamus using site-specific delivery of lentiviral shRNA against Atg7. This model revealed that hypothalamic inhibition of autophagy increased energy intake and reduced energy expenditure. These metabolic changes were sufficient to increase body weight gain under normal chow feeding and exacerbate the progression of obesity and whole-body insulin resistance under high-fat diet feeding. To explore the underlying mechanism, this study found that defective hypothalamic autophagy led to hypothalamic inflammation, including the activation of proinflammatory IκB kinase β pathway. Using brain-specific IκB kinase β knockout mice, it was found that the effects of defective hypothalamic autophagy in promoting obesity were reversed by IκB kinase β inhibition in the brain. In conclusion, hypothalamic autophagy is crucial for the central control of feeding, energy, and body weight balance. Conversely, decline of hypothalamic autophagy under conditions of chronic caloric excess promotes hypothalamic inflammation and thus impairs hypothalamic control of energy balance, leading to accelerated development of obesity and comorbidities.

Cardiotrophin-1 Is a Key Regulator of Glucose and Lipid Metabolism

Cardiotrophin-1 (CT-1) is a member of the gp130 family of cytokines. We observed that ct-1(-/-) mice develop mature-onset obesity, insulin resistance, and hypercholesterolemia despite reduced calorie intake. Decreased energy expenditure preceded and accompanied the development of obesity. Acute treatment with rCT-1 decreased blood glucose in an insulin-independent manner and increased insulin-stimulated AKT phosphorylation in muscle. These changes were associated with stimulation of fatty acid oxidation, an effect that was absent in AMPKα2(-/-) mice. Chronic rCT-1 treatment reduced food intake, enhanced energy expenditure, and induced white adipose tissue remodeling characterized by upregulation of genes implicated in the control of lipolysis, fatty acid oxidation, and mitochondrial biogenesis and genes typifying brown fat phenotype. Moreover, rCT-1 reduced body weight and corrected insulin resistance in ob/ob and in high-fat-fed obese mice. We conclude that CT-1 is a master regulator of fat and glucose metabolism with potential applications for treatment of obesity and insulin resistance.

Targeting Intermediary Metabolism in the Hypothalamus as a Mechanism to Regulate Appetite

The central nervous system mediates energy balance (energy intake and energy expenditure) in the body; the hypothalamus has a key role in this process. Recent evidence has demonstrated an important role for hypothalamic malonyl CoA in mediating energy balance. Malonyl CoA is generated by the carboxylation of acetyl CoA by acetyl CoA carboxylase and is then either incorporated into long-chain fatty acids by fatty acid synthase, or converted back to acetyl-CoA by malonyl CoA decarboxylase. Increased hypothalamic malonyl CoA is an indicator of energy surplus, resulting in a decrease in food intake and an increase in energy expenditure. In contrast, a decrease in hypothalamic malonyl CoA signals an energy deficit, resulting in an increased appetite and a decrease in body energy expenditure. A number of hormonal and neural orexigenic and anorexigenic signaling pathways have now been shown to be associated with changes in malonyl CoA levels in the arcuate nucleus (ARC) of the hypothalamus. Despite compelling evidence that malonyl CoA is an important mediator in the hypothalamic ARC control of food intake and regulation of energy balance, the mechanism(s) by which this occurs has not been established. Malonyl CoA inhibits carnitine palmitoyltransferase-1 (CPT-1), and it has been proposed that the substrate of CPT-1, long-chain acyl CoA(s), may act as a mediator(s) of appetite and energy balance. However, recent evidence has challenged the role of long-chain acyl CoA(s) in this process, as well as the involvement of CPT-1 in hypothalamic malonyl CoA signaling. A better understanding of how malonyl CoA regulates energy balance should provide novel approaches to targeting intermediary metabolism in the hypothalamus as a mechanism to control appetite and body weight. Here, we review the data supporting an important role for malonyl CoA in mediating hypothalamic control of energy balance, and recent evidence suggesting that targeting malonyl CoA synthesis or degradation may be a novel approach to favorably modify appetite and weight gain.

Moderate caloric restriction during gestation results in lower arcuate nucleus NPY‐ and αMSH‐neurons and impairs hypothalamic response to fed/fasting conditions in weaned rats

We aimed to characterize the developmental programming effects of moderate caloric restriction during early pregnancy on factors involved in hypothalamic control of energy balance. Twenty-five-days-old offspring Wistar rats from 20% caloric restricted dams (from 1 to 12 days of pregnancy) (CR) and from control dams were studied under fed and 12 h fasting conditions. Morphometric studies on arcuate nucleus (ARC) and determinations of circulating parameters and hypothalamic levels of neuropeptide Y (NPY), proopiomelanocortin (POMC), long-form leptin receptor (ObRb), insulin receptor (InsR) and suppressor of cytokine signalling-3 (SOCS-3) mRNA were performed. CR animals did not show different body weight with respect to their controls, but presented higher food intake. They exhibited lower neuropeptide Y- and alpha-melanocyte-stimulating hormone-neurons (decreases of 18 and 13% in males, and 10 and 18% in females respectively) and lower total cells (decrease of 3% in males and 18% in females) in ARC. Under fed conditions, CR animals presented lower circulating leptin and ghrelin levels (decreases of 37 and 43% in males, and 15 and 34% in females respectively); furthermore, hypothalamic POMC, NPY (only in females), ObRb and InsR mRNA levels were reduced (39, 16 and 26% in males, and 112, 33, 61 and 56% in females), and those of SOCS-3 were increased (86% in males and 74% in females). Unlike control animals, under fasting conditions, ObRb, InsR and POMC mRNA levels did not decrease in CR females, and NPY mRNA decreased instead of increase in CR males. Moderate caloric restriction during gestation affects offspring hypothalamic structure and function, impairing its response to fed/fasting conditions, which suggests a predisposition to insulin and leptin resistance.

Coordinated changes in energy intake and expenditure following hypothalamic administration of neuropeptides involved in energy balance

ObjectiveThe hypothalamic control of energy balance is regulated by a complex network of neuropeptide-releasing neurons. Whilst the effect of these neuropeptides on individual aspects of energy homeostasis has been studied, the coordinated response of these effects has not been comprehensively investigated. We have simultaneously monitored a number of metabolic parameters following ICV administration of 1nmol and 3nmol of neuropeptides with established roles in the regulation of feeding, activity and metabolism. Ad libitum fed rats received the orexigenic neuropeptides neuropeptide Y (NPY), agouti-related protein (AgRP), melanin-concentrating hormone (MCH) or orexin-A. Overnight food deprived rats received an ICV injection of the anorectic peptides α-MSH, corticotrophin releasing factor (CRF) or neuromedin U (NMU).ResultsOur results reveal the temporal sequence of the effects of these neuropeptides on both energy intake and expenditure, highlighting key differences in their function as mediators of energy balance. NPY and AgRP increased feeding and decreased oxygen consumption, with the effects of AgRP being more prolonged. In contrast, orexin-A increased both feeding and oxygen consumption, consistent with an observed increase in activity. The potent anorexigenic effects of CRF were accompanied by a prolonged increase in activity whilst NMU injection resulted in significant but short-lasting inhibition of food intake, ambulatory activity and oxygen consumption. Alpha-MSH injection resulted in significant increases in both ambulatory activity and oxygen consumption, and reduced food intake following administration of 3nmol of the peptide.ConclusionWe have for the first time, simultaneously measured several metabolic parameters following hypothalamic administration of a number of neuropeptides within the same experimental system. This work has demonstrated the interrelated effects of these neuropeotides on activity, energy expenditure and food intake thus facilitating comparison between the different hypothalamic systems.

Downstream signaling mechanisms of arcuate nucleus malonyl-CoA in the hypothalamic control of energy balance

Downstream signaling mechanisms of arcuate nucleus malonyl-CoA in the hypothalamic control of energy balance

Hypothalamic Reactive Oxygen Species Are Required for Insulin-Induced Food Intake Inhibition

OBJECTIVEInsulin plays an important role in the hypothalamic control of energy balance, especially by reducing food intake. Emerging data point to a pivotal role of reactive oxygen species (ROS) in energy homeostasis regulation, but their involvement in the anorexigenic effect of insulin is unknown. Furthermore, ROS signal derived from NADPH oxidase activation is required for physiological insulin effects in peripheral cells. In this study, we investigated the involvement of hypothalamic ROS and NADPH oxidase in the feeding behavior regulation by insulin.RESEARCH DESIGN AND METHODSWe first measured hypothalamic ROS levels and food intake after acute intracerebroventricular injection of insulin. Second, effect of pretreatment with a ROS scavenger or an NADPH oxidase inhibitor was evaluated. Third, we examined the consequences of two nutritional conditions of central insulin unresponsiveness (fasting or short-term high-fat diet) on the ability of insulin to modify ROS level and food intake.RESULTSIn normal chow-fed mice, insulin inhibited food intake. At the same dose, insulin rapidly and transiently increased hypothalamic ROS levels by 36%. The pharmacological suppression of this insulin-stimulated ROS elevation, either by antioxidant or by an NADPH oxidase inhibitor, abolished the anorexigenic effect of insulin. Finally, in fasted and short-term high-fat diet–fed mice, insulin did not promote elevation of ROS level and food intake inhibition, likely because of an increase in hypothalamic diet-induced antioxidant defense systems.CONCLUSIONSA hypothalamic ROS increase through NADPH oxidase is required for the anorexigenic effect of insulin.

Hypothalamic neurodegeneration and adult-onset obesity in mice lacking the Ubb polyubiquitin gene

Nearly all neurodegenerative diseases are associated with abnormal accumulation of ubiquitin (Ub) conjugates within neuronal inclusion bodies. To directly test the hypothesis that depletion of cellular Ub is sufficient to cause neurodegeneration, we have disrupted Ubb, one of four genes that supply Ub in the mouse. Here, we report that loss of Ubb led to a progressive degenerative disorder affecting neurons within the arcuate nucleus of the hypothalamus. This neurodegenerative cytopathology was accompanied by impaired hypothalamic control of energy balance and adult-onset obesity. Ubb was highly expressed in vulnerable hypothalamic neurons and total Ub levels were selectively reduced in the hypothalamus of Ubb-null mice. These findings demonstrate that maintenance of adequate supplies of cellular Ub is essential for neuronal survival and establish that decreased Ub availability is sufficient to cause neuronal dysfunction and death.

“AMPing up” our understanding of the hypothalamic control of energy balance

AMP-activated protein kinase (AMPK) has emerged as a metabolic "fuel gauge," which oscillates between anabolic and catabolic processes that ultimately influence energy balance. A study in this issue of the JCI by Claret et al. now extends the role of AMPK in medial basal hypothalamic neurons (see the related article beginning on page 2325). These findings maintain AMPK signaling as a common cellular mechanism in proopiomelanocortin and neuropeptide Y/agouti-related protein neurons and links hypothalamic AMPK to coordinated energy and glucose homeostasis.

Shp2 as a therapeutic target for leptin resistance and obesity

Most obese subjects exhibit leptin resistance, thus restricting the value of direct leptin administration for treatment of obesity. Understanding the leptin signalling mechanism has become crucial for design of novel therapeutic strategies for leptin-resistant/obese patients. The SH2-containing cytoplasmic tyrosine phosphatase Shp2 has recently been shown to play a critical role in leptin signalling and functions in hypothalamic control of energy balance and metabolism. Shp2 appears to downregulate the LepRb-STAT3 pathway while promoting extracellular-regulated kinase activation by leptin. Overall, Shp2 is a leptin signal enhancer, as evidenced by the obese and hyperleptinemic phenotype of mutant mice with Shp2 deleted in postmitotic forebrain neurons. Pharmaceutical enhancement of Shp2 activity may be a new approach worthy of consideration in clinical treatment of leptin resistance and obesity. This article discusses the significance of recent experimental data on Shp2 and also the prospects for using Shp2 as a therapeutic target for obese patients.