Type 5 adenylyl cyclase disruption leads to enhanced exercise performance

The most important physiological mechanism mediating enhanced exercise performance is increased sympathetic, beta adrenergic receptor (β‐AR), and adenylyl cyclase (AC) activity. This is the first report of decreased AC activity mediating increased exercise performance. We demonstrated that AC5 disruption, that is, knock out (KO) mice, a longevity model, increases exercise performance. Importantly for its relation to longevity, exercise was also improved in old AC5 KO. The mechanism resided in skeletal muscle rather than in the heart, as confirmed by cardiac‐ and skeletal muscle‐specific AC5 KO's, where exercise performance was no longer improved by the cardiac‐specific AC5 KO, but was by the skeletal muscle‐specific AC5 KO, and there was no difference in cardiac output during exercise in AC5 KO vs. WT. Mitochondrial biogenesis was a major mechanism mediating the enhanced exercise. SIRT1, FoxO3a, MEK, and the anti‐oxidant, MnSOD were upregulated in AC5 KO mice. The improved exercise in the AC5 KO was blocked with either a SIRT1 inhibitor, MEK inhibitor, or by mating the AC5 KO with MnSOD hetero KO mice, confirming the role of SIRT1, MEK, and oxidative stress mechanisms. The Caenorhabditis elegans worm AC5 ortholog, acy‐3 by RNAi, also improved fitness, mitochondrial function, antioxidant defense, and lifespan, attesting to the evolutionary conservation of this pathway. Thus, decreasing sympathetic signaling through loss of AC5 is not only a mechanism to improve exercise performance, but is also a mechanism to improve healthful aging, as exercise also protects against diabetes, obesity, and cardiovascular disease, which all limit healthful aging.     

Prevention of heart failure in mice by an antiviral agent that inhibits type 5 cardiac adenylyl cyclase

Despite numerous discoveries from genetically engineered mice, relatively few have been translated to the bedside, mainly because it is difficult to translate from genes to drugs. This investigation examines an antiviral drug, which also has an action to selectively inhibit type 5 adenylyl cyclase (AC5), a pharmaceutical correlate of the AC5 knockout (KO) model, which exhibits longevity and stress resistance. Our objective was to examine the extent to which pretreatment with this drug, adenine 9-β-d-arabinofuranoside (Ara-A), favorably ameliorates the development of heart failure (HF). Ara-A exhibited selective inhibition for AC5 compared with the other major cardiac AC isoform, AC6, i.e., it reduced AC activity significantly in AC5 transgenic (Tg) mice, but not in AC5KO mice and had little effect in either wild-type or AC6Tg mice. Permanent coronary artery occlusion for 3 wk in C57Bl/6 mice increased mortality and induced HF in survivors, as reflected by reduced cardiac function, while increasing cardiac fibrosis. The AC5 inhibitor Ara-A significantly improved all of these end points and also ameliorated chronic isoproterenol-induced cardiomyopathy. As with the AC5KO mice, Ara-A increased mitogen/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation. A MEK inhibitor abolished the beneficial effects of the AC5 inhibitor in the HF model, indicating the involvement of the downstream MEK-ERK pathway of AC5. Our data suggest that pharmacological AC5 inhibition may serve as a new therapeutic approach for HF.     

Type 5 adenylyl cyclase disruption increases longevity and protects against stress

Mammalian models of longevity are related primarily to caloric restriction and alterations in metabolism. We examined mice in which type 5 adenylyl cyclase (AC5) is knocked out (AC5 KO) and which are resistant to cardiac stress and have increased median lifespan of approximately 30%. AC5 KO mice are protected from reduced bone density and susceptibility to fractures of aging. Old AC5 KO mice are also protected from aging-induced cardiomyopathy, e.g., hypertrophy, apoptosis, fibrosis, and reduced cardiac function. Using a proteomic-based approach, we demonstrate a significant activation of the Raf/MEK/ERK signaling pathway and upregulation of cell protective molecules, including superoxide dismutase. Fibroblasts isolated from AC5 KO mice exhibited ERK-dependent resistance to oxidative stress. These results suggest that AC is a fundamentally important mechanism regulating lifespan and stress resistance.     

Common mechanisms for calorie restriction and adenylyl cyclase type 5 knockout models of longevity

Adenylyl cyclase type 5 knockout mice (AC5 KO) live longer and are stress resistant, similar to calorie restriction (CR). AC5 KO mice eat more, but actually weigh less and accumulate less fat compared with WT mice. CR applied to AC5 KO results in rapid decrease in body weight, metabolic deterioration, and death. These data suggest that despite restricted food intake in CR, but augmented food intake in AC5 KO, the two models affect longevity and metabolism similarly. To determine shared molecular mechanisms, mRNA expression was examined genome‐wide for brain, heart, skeletal muscle, and liver. Significantly more genes were regulated commonly rather than oppositely in all the tissues in both models, indicating commonality between AC5 KO and CR. Gene ontology analysis identified many significantly regulated, tissue‐specific pathways shared by the two models, including sensory perception in heart and brain, muscle function in skeletal muscle, and lipid metabolism in liver. Moreover, when comparing gene expression changes in the heart under stress, the glutathione regulatory pathway was consistently upregulated in the longevity models but downregulated with stress. In addition, AC5 and CR shared changes in genes and proteins involved in the regulation of longevity and stress resistance, including Sirt1, ApoD, and olfactory receptors in both young‐ and intermediate‐age mice. Thus, the similarly regulated genes and pathways in AC5 KO and CR mice, particularly related to the metabolic phenotype, suggest a unified theory for longevity and stress resistance.     

PAPP‐A: a new anti‐aging target?

This article focuses on the role of PAPP‐A in mammalian aging. It introduces PAPP‐A and a little of its history, briefly discusses the function of PAPP‐A in the insulin‐like growth factor (IGF) system and the regulators of PAPP‐A expression, and then reviews data concerning PAPP‐A in aging and age‐related diseases especially in regard to the PAPP‐A knockout (KO) mouse. The PAPP‐A KO mouse is a valuable new model to test hypotheses concerning the control of the tissue availability of IGF, independent from systemic levels, on healthspan as well as lifespan.     

Inducible knockdown of pregnancy‐associated plasma protein‐A gene expression in adult female mice extends life span

Pregnancy‐associated plasma protein‐A (PAPP‐A) knockout (KO) mice, generated through homologous recombination in embryonic stem cells, have a significantly increased lifespan compared to wild‐type littermates. However, it is unknown whether this longevity advantage would pertain to PAPP‐A gene deletion in adult animals. In the present study, we used tamoxifen (Tam)‐inducible Cre recombinase‐mediated excision of the floxed PAPP‐A (fPAPP‐A) gene in mice at 5 months of age. fPAPP‐A mice, which were either positive (pos) or negative (neg) for Tam‐Cre, received Tam treatment with quarterly boosters. Only female mice could be used with this experimental design. fPAPP‐A/neg and fPAPP‐A/pos mice had similar weights at the start of the experiment and showed equivalent weight gain. We found that fPAPP‐A/pos mice had a significant extension of life span (P = 0.005). The median life span was increased by 21% for fPAPP‐A/pos compared to fPAPP‐A/neg mice. Analysis of mortality in life span quartiles indicated that the proportion of deaths of fPAPP‐A/pos mice were lower than fPAPP‐A/neg mice at young adult ages (P = 0.002 for 601–800 days) and higher than fPAPP‐A/neg mice at older ages (P = 0.004 for >1000 days). Thus, survival curves and age‐specific mortality indicate that female mice with knockdown of PAPP‐A gene expression as adults have an extended healthy life span.     

The growth hormone receptor gene‐disrupted mouse fails to respond to an intermittent fasting diet

The interaction of longevity‐conferring genes with longevity‐conferring diets is poorly understood. The growth hormone receptor gene‐disrupted (GHR‐KO) mouse is long lived; and this longevity is not responsive to 30% caloric restriction, in contrast to wild‐type animals from the same strain. To determine whether this may have been limited to a particular level of dietary restriction, we subjected GHR‐KO mice to a different dietary restriction regimen, an intermittent fasting diet. The intermittent fasting diet increased the survivorship and improved insulin sensitivity of normal males, but failed to affect either parameter in GHR‐KO mice. From the results of two paradigms of dietary restriction, we postulate that GHR‐KO mice would be resistant to any manner of dietary restriction; potentially due to their inability to further enhance insulin sensitivity. Insulin sensitivity may be a mechanism and/or a marker of the lifespan extending potential of an intervention.     

Deficiency of sterol regulatory element‐binding protein‐1c induces schizophrenia‐like behavior in mice

Schizophrenia is a hereditary disease that approximately 1% of the worldwide population develops. Many studies have investigated possible underlying genes related to schizophrenia. Recently, clinical studies suggested sterol regulatory element‐binding protein (SREBP) as a susceptibility gene in patients with schizophrenia. SREBP controls cellular lipid homeostasis by three isoforms: SREBP‐1a, SREBP‐1c and SREBP‐2. This study used SREBP‐1c knockout (KO) mice to examine whether a deficiency in SREBP‐1c would affect their emotional and psychiatric behaviors. Altered mRNA expression in genes downstream from SREBP‐1c was confirmed in the brains of SREBP‐1c KO mice. Schizophrenia‐like behavior, including hyperactivity during the dark phase, depressive‐like behavior, aggressive behavior and deficits in social interaction and prepulse inhibition, was observed in SREBP‐1c KO mice. Furthermore, increased volume of the lateral ventricle was detected in SREBP‐1c KO mice. The mRNA levels of several γ‐aminobutyric acid (GABA)‐receptor subtypes and/or glutamic acid decarboxylase 65/67 decreased in the hippocampus and medial prefrontal cortex of SREBP‐1c KO mice. Thus, SREBP‐1c deficiency may contribute to enlargement of the lateral ventricle and development of schizophrenia‐like behaviors and be associated with altered GABAergic transmission.     

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

Disruption of the regulator for G protein signaling 14 (RGS14) knockout (KO) in mice extends their lifespan and has multiple beneficial effects related to healthful aging, that is, protection from obesity, as reflected by reduced white adipose tissue, protection against cold exposure, and improved metabolism. The observed beneficial effects were mediated by improved mitochondrial function. But most importantly, the main mechanism responsible for the salutary properties of the RGS14 KO involved an increase in brown adipose tissue (BAT), which was confirmed by surgical BAT removal and transplantation to wild‐type (WT) mice, a surgical simulation of a molecular knockout. This technique reversed the phenotype of the RGS14 KO and WT, resulting in loss of the improved metabolism and protection against cold exposure in RGS14 KO and conferring this protection to the WT BAT recipients. Another mechanism mediating the salutary features in the RGS14 KO was increased SIRT3. This mechanism was confirmed in the RGS14 X SIRT3 double KO, which no longer demonstrated improved metabolism and protection against cold exposure. Loss of function of the Caenorhabditis elegans RGS‐14 homolog confirmed the evolutionary conservation of this mechanism. Thus, disruption of RGS14 is a model of healthful aging, as it not only enhances lifespan, but also protects against obesity and cold exposure and improves metabolism with a key mechanism of increased BAT, which, when removed, eliminates the features of healthful aging.     

Role of aquaporin 5 in antigen‐induced airway inflammation and mucous hyperproduction in mice

Airway inflammation and mucus hyperproduction play the central role in the development of asthma, although the mechanisms remain unclear. The aquaporin (AQP)‐5 may be involved in the process due to its contribution to the volume of liquid secreted from the airways. The present study firstly found the overexpression of AQP5 in the airway epithelium and submucosal glands of asthmatics. Furthermore, we aimed at evaluating the role of AQP5 in airway inflammation and mucous hyperproductions during chronic allergic responses to house dust mite (HDM). Bronchoalveolar lavage levels of interleukin (IL)‐2, IL‐4, IL‐10, interferon‐γ and Mucin 5AC (MUC5AC), and number of peribronchial and perivascular cells were measured in AQP5 wild‐type and AQP5 knockout (KO) mice. We found that HDM induced airway inflammation, lung Th2 cell accumulation and mucin hypersecretion in C57BL/6 mice rather than AQP5 KO mice. Expression of MUC5AC and MUC5B proteins and genes in the lung tissue was significantly lower in AQP5 KO mice. Thus, our results implicate involvement of AQP5 in the development of airway inflammation and mucous hyperproduction during chronic asthma.     

Transient receptor potential ankyrin 1 (TRPA1) positively regulates imiquimod‐induced,psoriasiform dermal inflammation in mice

Transient receptor potential ankyrin 1 (TRPA1), a membrane protein ion channel, is known to mediate itch and pain in skin. The function of TRPA1, however, in psoriasiform dermatitis (PsD) is uncertain. Herein, we found that expression of TRPA1 is highly up‐regulated in human psoriatic lesional skin. To study the role of TRPA1 in PsD, we assessed Psoriasis Severity Index (PSI) scores, transepidermal water loss (TEWL), skin thickness and pathology, and examined dermal inflammatory infiltrates, Th17‐related genes and itch‐related genes in c57BL/6 as wild‐type (WT) and TRPA1 gene knockout (KO) mice following daily application of topical IMQ cream for 5 days. Compared with WT mice, clinical scores, skin thickness change and TEWL scores were similar on day 3, but were significantly decreased on day 5 in IMQ‐treated TRPA1 KO mice (vs WT mice), suggesting reduced inflammation and skin barrier defects. Additionally, the relative area of epidermal Munro's microabscesses and mRNA levels of neutrophil inducible chemokines (S100A8, S100A9 and CXCL1) were decreased in the treated skin of TRPA1 KO mice, suggesting that neutrophil recruitment was impaired in the KO mice. Furthermore, mast cells, CD31⁺ blood vascular cells, CD45⁺ leukocytes and CD3⁺ T cells were all reduced in the treated skin of TRPA1 KO mice. Lastly, mRNA expression levels of IL‐1β, IL‐6, IL‐23, IL‐17A, IL‐17F and IL‐22 were decreased in TRPA1 KO mice. In summary, these results suggest a key role for TRPA1 in psoriasiform inflammation and raising its potential as a target for therapeutic intervention.     

Tumor necrosis factor receptor‐associated factor 5 is an essential mediator of ischemic brain infarction

Tumor necrosis factor receptor‐associated factor 5 (TRAF5) is an adaptor protein of the tumor necrosis factor (TNF) receptor superfamily and the interleukin‐1 receptor/Toll‐like receptor superfamily and plays important roles in regulating multiple signaling pathways. This study was conducted to investigate the role of TRAF5 in the context of brain ischemia/reperfusion (I/R) injury. Transient occlusion of the middle cerebral artery was performed on TRAF5 knockout mice (KO), neuron‐specific TRAF5 transgene (TG), and the appropriate controls. Compared with the WT mice, the TRAF5 KO mice showed lower infarct volumes and better outcomes in the neurological tests. A low neuronal apoptosis level, an attenuated blood‐brain barrier (BBB) disruption and an inhibited inflammatory response were exhibited in TRAF5 KO mice. TRAF5 TG mice exhibited an opposite phenotype. Moreover, the Akt/FoxO1 signaling pathway was enhanced in the ischemic brains of the TRAF5 KO mice. These results provide the first demonstration that TRAF5 is a critical mediator of I/R injury in an experimental stroke model. The Akt /FoxO1 signaling pathway probably plays an important role in the biological function of TRAF5 in this model.     

Intrinsically altered lung‐resident γδT cells control lung melanoma by producing interleukin‐17A in the elderly

Cancer is an age‐associated disease, potentially related to the altered immune system of elderly individuals. However, cancer has gradually decreased incidence in the eldest globally such as the most common lung cancer, the mechanisms of which remain to be elucidated. In this study, it was found that the number of lung‐resident γδT cells was significantly increased with altered gene expression in aged mice (20–24 months) versus young mice (10–16 weeks). Aged lung Vγ4⁺ and Vγ6⁺ γδT cells predominantly produced interleukin‐17A (IL‐17A), resulting in increased levels in the serum and lungs. Moreover, the aged mice exhibited smaller tumors and reduced numbers of tumor foci in the lungs after challenge with intravenous injection of B16/F10 melanoma cells compared with the young mice. Aged lung Vγ4⁺ and Vγ6⁺ γδT cells were highly cytotoxic to B16/F10 melanoma cells with higher expression levels of CD103. The markedly longer survival of the challenged aged mice was dependent on γδT17 cells, since neutralization of IL‐17A or depletion of indicated γδT cells significantly shortened the survival time. Consistently, supplementation of IL‐17A significantly enhanced the survival time of young mice with lung melanoma. Furthermore, the anti‐tumor activity of aged lung γδT17 cells was not affected by alterations in the load and composition of commensal microbiota, as demonstrated through co‐housing of the aged and young mice. Intrinsically altered lung γδT17 cells underlying age‐dependent changes control lung melanoma, which will help to better understand the lung cancer progression in the elderly and the potential use of γδT17 cells in anti‐tumor immunotherapy.     

Behavioral characterization of striatal‐enriched protein tyrosine phosphatase (STEP) knockout mice

Striatal‐enriched protein tyrosine phosphatase (STEP) has been described as a regulator of multiple kinases and glutamate receptor subunits critical for synaptic plasticity. Published behavioral and biochemical characterization from the founder line of STEP knockout (KO) mice revealed superior cognitive performance, with enhanced phosphorylation of substrates such as ERK, Fyn and GluN2B; suggesting that inhibitors of STEP may have potential as therapeutic agents for the treatment of neuropsychiatric disorders. The objectives of this work aimed to replicate and extend the previously reported behavioral consequences of STEP knockout. Consistent with previous reported data, STEP KO mice demonstrated exploratory activity levels and similar motor coordination relative to WT littermate controls as well as intact memory in a Y‐maze spatial novelty test. Interestingly, KO mice demonstrated deficits in pre‐pulse inhibition as well as reduced seizure threshold relative to WT controls. Immunohistochemical staining of brains revealed the expected gene‐dependent reduction in STEP protein confirming knockout in the mice. The present data confirm expression and localization of STEP and the absence in KO mice, and describe functional downstream implications of reducing STEP levels in vivo.     

Physiological and metabolic characteristics of novel double‐mutant female mice with targeted disruption of both growth hormone‐releasing hormone and growth hormone receptor

Mice with disruptions of growth hormone‐releasing hormone (GHRH) or growth hormone receptor (GHR) exhibit similar phenotypes of prolonged lifespan and delayed age‐related diseases. However, these two models respond differently to calorie restriction indicating that they might carry different and/or independent mechanisms for improved longevity and healthspan. In order to elucidate these mechanisms, we generated GHRH and GHR double‐knockout mice (D‐KO). In the present study, we focused specifically on the characteristics of female D‐KO mice. The D‐KO mice have reduced body weight and enhanced insulin sensitivity compared to wild‐type (WT) controls. Growth retardation in D‐KO mice is accompanied by decreased GH expression in pituitary, decreased circulating IGF‐1, increased high‐molecular‐weight (HMW) adiponectin, and leptin hormones compared to WT controls. Generalized linear model‐based regression analysis, which controls for body weight differences between D‐KO and WT groups, shows that D‐KO mice have decreased lean mass, bone mineral density, and bone mineral content, but increased adiposity. Indirect calorimetry markers including oxygen consumption, carbon dioxide production, and energy expenditure were significantly lower in D‐KO mice relative to the controls. In comparison with WT mice, the D‐KO mice displayed reduced respiratory exchange ratio (RER) values only during the light cycle, suggesting a circadian‐related metabolic shift toward fat utilization. Interestingly, to date survival data suggest extended lifespan in D‐KO female mice.     

Longevity and skeletal muscle mass: the role of IGF signalling,the sirtuins,dietary restriction and protein intake

Advancing age is associated with a progressive loss of skeletal muscle (SkM) mass and function. Given the worldwide aging demographics, this is a major contributor to morbidity, escalating socio‐economic costs and ultimately mortality. Previously, it has been established that a decrease in regenerative capacity in addition to SkM loss with age coincides with suppression of insulin/insulin‐like growth factor signalling pathways. However, genetic or pharmacological modulations of these highly conserved pathways have been observed to significantly enhance life and healthspan in various species, including mammals. This therefore provides a controversial paradigm in which reduced regenerative capacity of skeletal muscle tissue with age potentially promotes longevity of the organism. This paradox will be assessed and considered in the light of the following: (i) the genetic knockout, overexpression and pharmacological models that induce lifespan extension (e.g. IRS‐1/s6K KO, mTOR inhibition) versus the important role of these signalling pathways in SkM growth and adaptation; (ii) the role of the sirtuins (SIRTs) in longevity versus their emerging role in SkM regeneration and survival under catabolic stress; (iii) the role of dietary restriction and its impact on longevity versus skeletal muscle mass regulation; (iv) the crosstalk between cellular energy metabolism (AMPK/TSC2/SIRT1) and survival (FOXO) versus growth and repair of SkM (e.g. AMPK vs. mTOR); and (v) the impact of protein feeding in combination with dietary restriction will be discussed as a potential intervention to maintain SkM mass while increasing longevity and enabling healthy aging.     

Hic‐5 deficiency protects cerulein‐induced chronic pancreatitis via down‐regulation of the NF‐κB (p65)/IL‐6 signalling pathway

Chronic pancreatitis (CP), characterized by pancreatic fibrosis, is a recurrent, progressive and irreversible disease. Activation of the pancreatic stellate cells (PSCs) is considered a core event in pancreatic fibrosis. In this study, we investigated the role of hydrogen peroxide‐inducible clone‐5 (Hic‐5) in CP. Analysis of the human pancreatic tissue samples revealed that Hic‐5 was overexpressed in patients with CP and was extremely low in healthy pancreas. Hic‐5 was significant up‐regulated in the activated primary PSCs independently from transforming growth factor beta stimulation. CP induced by cerulein injection was ameliorated in Hic‐5 knockout (KO) mice, as shown by staining of tissue level. Simultaneously, the activation ability of the primary PSCs from Hic‐5 KO mice was significantly attenuated. We also found that the Hic‐5 up‐regulation by cerulein activated the NF‐κB (p65)/IL‐6 signalling pathway and regulated the downstream extracellular matrix (ECM) genes such as α‐SMA and Col1a1. Therefore, we determined whether suppressing NF‐κB/p65 alleviated CP by treating mice with the NF‐κB/p65 inhibitor triptolide in the cerulein‐induced CP model and found that pancreatic fibrosis was alleviated by NF‐κB/p65 inhibition. These findings provide evidence for Hic‐5 as a therapeutic target that plays a crucial role in regulating PSCs activation and pancreatic fibrosis.     

Specific suppression of insulin sensitivity in growth hormone receptor gene‐disrupted (GHR‐KO) mice attenuates phenotypic features of slow aging

In addition to their extended lifespans, slow‐aging growth hormone receptor/binding protein gene‐disrupted (knockout) (GHR‐KO) mice are hypoinsulinemic and highly sensitive to the action of insulin. It has been proposed that this insulin sensitivity is important for their longevity and increased healthspan. We tested whether this insulin sensitivity of the GHR‐KO mouse is necessary for its retarded aging by abrogating that sensitivity with a transgenic alteration that improves development and secretory function of pancreatic β‐cells by expressing Igf‐1 under the rat insulin promoter 1 (RIP::IGF‐1). The RIP::IGF‐1 transgene increased circulating insulin content in GHR‐KO mice, and thusly fully normalized their insulin sensitivity, without affecting the proliferation of any non‐β‐cell cell types. Multiple (nonsurvivorship) longevity‐associated physiological and endocrinological characteristics of these mice (namely beneficial blood glucose regulatory control, altered metabolism, and preservation of memory capabilities) were partially or completely normalized, thus supporting the causal role of insulin sensitivity for the decelerated senescence of GHR‐KO mice. We conclude that a delayed onset and/or decreased pace of aging can be hormonally regulated.     

Obesity in Insulin Receptor Substrate‐2–Deficient Mice: Disrupted Control of Arcuate Nucleus Neuropeptides

Objectives : Disturbances in insulin signaling have been shown to induce obesity and/or hyperphagia in brain insulin receptor or insulin receptor substrate‐2 (IRS‐2) knockout (KO) mice. This study aimed to examine the central and peripheral mechanisms underlying the phenotype in IRS‐2 KO mice. Research Methods and Procedures : We measured the histological characterization of adipose tissues, mRNA levels of pro‐opiomelanocortin, agouti‐related protein, and neuropeptide Y in the hypothalamus and uncoupling proteins (UCPs) in peripheral tissues of IRS‐2 KO mice. Results : Female IRS‐2 KO mice showed increased daily food intake. Body weight and adiposity were increased in both sexes, although these differences were more pronounced in female than in male IRS‐2 KO mice. Both male and female IRS‐2 KO mice showed decreased UCP1 mRNA expression in brown adipose tissue with defective thermoregulation, and UCP2 mRNA expression was increased in the white adipose tissue of female knockout mice. Furthermore, arcuate nucleus mRNA expression of pro‐opiomelanocortin, was decreased in both male and female IRS‐2 KO mice, whereas expression of agouti‐related protein and neuropeptide Y were increased in female IRS‐2 KO mice. Discussion : In IRS‐2 KO mice, disrupted control of hypothalamic neuropeptide levels and UCP mRNA expression may contribute to the development of obesity.