Hypothalamic Appetite Control Research Articles

Interleukin-4 inhibits the hypothalamic appetite control by modulating the insulin-AKT and JAK-STAT signaling in leptin mutant mice.

Our previous research identified interleukin-4 (IL-4) as a key regulator of glucose/lipid metabolism, circulatory leptin levels, and insulin action, suggesting its potential as a therapeutic target for obesity and related complications. This study aimed to further elucidate the role of IL-4 in regulating hypothalamic appetite-controlling neuropeptides using leptin dysfunctional Leptin145E/145E mice as the experimental model. IL-4 significantly reduces body weight, food intake, and serum glucose levels. Our data demonstrated that IL-4 exhibits multiple functions in regulating hypothalamic appetite control, including downregulating orexigenic agouti-related peptide and neuropeptide Y levels, promoting expression of anorexigenic proopiomelanocortin, alleviating microenvironmental hypothalamic inflammation, enhancing leptin and insulin pathway, and attenuating insulin resistance. Furthermore, IL-4 promotes uncoupling protein 1 expression of white adipose tissue (WAT), suggesting its role in triggering WAT-beige switch. In summary, this study uncovers novel function of IL-4 in mediating food-intake behaviors and metabolic efficiency by regulating hypothalamic appetite-control and WAT browning activities. These findings support the therapeutic potential of targeting hypothalamic inflammation and reducing adiposity through IL-4 intervention for tackling the pandemic increasing prevalence of obesity and associated metabolic disorders.

Differential sex-association between PCSK1 polymorphisms and obesity risk in Portuguese children.

The proprotein convertase subtilisin/Kexin type 1 gene (PCSK1) is implicated in hypothalamic appetite control. Several studies have addressed the relationship between PCSK1 polymorphisms and obesity, although conflicting results were observed. We tested the potential association of four PCSK1 variants with the risk of overweight/obesity and related variables in Portuguese children. This is a case-control study, where four PCSK1 variants, rs6230 (c.-101T>C), rs6232 (p.N221D), rs6235 (p.S690T), and rs3811942 (c.*265T>C), were analyzed in Portuguese children (aged 5-13 years-old). Anthropometric measures were objectively collected and used to provide weight-for-age, height-for-age, and body mass index (BMI) for age. The indices generated were compared to standard reference values of WHO to obtain the corresponding Z-scores. Logistic regression, in the dominant model, revealed no significant associations between the four individual PCSK1 variants and the risk of overweight/obesity in the total population. However, stratifying the sample by sex, a marginally significant association was found between the rs6235 minor C-allele and increased overweight/obesity in boys (n = 345) (OR 1.55 [1.01-2.38] p = .044), but not in girls (n = 340) (OR 0.73 [0.46-1.14] p = .169). Consistently, boys with genotype GG presented lower BMI Z-score (0.62) when compared to those with the genotypes GC + CC (1.04). Testing for different effects in males versus females, a significant interaction was found between the rs6235 polymorphism and sex for BMI Z-score (p = .025). Results of this study suggest for a sex-differentiated association between PCSK1 rs6235 and overweight/ obesity in Portuguese children.

Whole Transcriptome Analysis of Hypothalamus in Mice during Short-Term Starvation

Molecular profiling of the hypothalamus in response to metabolic shifts is a critical cue to better understand the principle of the central control of whole-body energy metabolism. The transcriptional responses of the rodent hypothalamus to short-term calorie restriction have been documented. However, studies on the identification of hypothalamic secretory factors that potentially contribute to the control of appetite are lacking. In this study, we analyzed the differential expression of hypothalamic genes and compared the selected secretory factors from the fasted mice with those of fed control mice using bulk RNA-sequencing. We verified seven secretory genes that were significantly altered in the hypothalamus of fasted mice. In addition, we determined the response of secretory genes in cultured hypothalamic cells to treatment with ghrelin and leptin. The current study provides further insights into the neuronal response to food restriction at the molecular level and may be useful for understanding the hypothalamic control of appetite.

Energy homeostasis deregulation is attenuated by TUDCA treatment in streptozotocin-induced Alzheimer\u2019s disease mice model

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. While cognitive deficits remain the major manifestation of AD, metabolic and non-cognitive abnormalities, such as alterations in food intake, body weight and energy balance are also present, both in AD patients and animal models. In this sense, the tauroursodeoxycholic acid (TUDCA) has shown beneficial effects both in reducing the central and cognitive markers of AD, as well as in attenuating the metabolic disorders associated with it. We previously demonstrated that TUDCA improves glucose homeostasis and decreases the main AD neuromarkers in the streptozotocin-induced AD mouse model (Stz). Besides that, TUDCA-treated Stz mice showed lower body weight and adiposity. Here, we investigated the actions of TUDCA involved in the regulation of body weight and adiposity in Stz mice, since the effects of TUDCA in hypothalamic appetite control and energy homeostasis have not yet been explored in an AD mice model. The TUDCA-treated mice (Stz + TUDCA) displayed lower food intake, higher energy expenditure (EE) and respiratory quotient. In addition, we observed in the hypothalamus of the Stz + TUDCA mice reduced fluorescence and gene expression of inflammatory markers, as well as normalization of the orexigenic neuropeptides AgRP and NPY expression. Moreover, leptin-induced p-JAK2 and p-STAT3 signaling in the hypothalamus of Stz + TUDCA mice was improved, accompanied by reduced acute food intake after leptin stimulation. Taken together, we demonstrate that TUDCA treatment restores energy metabolism in Stz mice, a phenomenon that is associated with reduced food intake, increased EE and improved hypothalamic leptin signaling. These findings suggest treatment with TUDCA as a promising therapeutic intervention for the control of energy homeostasis in AD individuals.

Upregulation of Mir342 in Diet-Induced Obesity Mouse and the Hypothalamic Appetite Control.

In obesity and type 2 diabetes, numerous genes are differentially expressed, and microRNAs are involved in transcriptional regulation of target mRNAs, but miRNAs critically involved in the appetite control are not known. Here, we identified upregulation of miR-342-3p and its host gene Evl in brain and adipose tissues in C57BL/6 mice fed with high fat-high sucrose (HFHS) chow by RNA sequencing. Mir342 (-/-) mice fed with HFHS chow were protected from obesity and diabetes. The hypothalamic arcuate nucleus neurons co-express Mir342 and EVL. The percentage of activated NPY+pSTAT3+ neurons were reduced, while POMC+pSTAT3+ neurons increased in Mir342 (-/-) mice, and they demonstrated the reduction of food intake and amelioration of metabolic phenotypes. Snap25 was identified as a major target gene of miR-342-3p and the reduced expression of Snap25 may link to functional impairment hypothalamic neurons and excess of food intake. The inhibition of miR-342-3p may be a potential candidate for miRNA-based therapy.

Circadian Clocks, Sleep, and Metabolism.

A molecular circadian clock exists not only in the brain, but also in most cells of the body. Research over the past two decades has demonstrated that it directs daily rhythmicity of nearly every aspect of metabolism. It also consolidates sleep-wake behavior each day into an activity/feeding period and a sleep/fasting period. Otherwise, sleep-wake states are mostly controlled by hypothalamic and thalamic regulatory circuits in the brain that direct overall brain state. Recent evidence suggests that hypothalamic control of appetite and metabolism may be concomitant with sleep-wake regulation, and even share the same control centers. Thus, circadian control of metabolic pathways might be overlaid by sleep-wake control of the same pathways, providing a flexible and redundant system to modify metabolism according to both activity and environment.

A Primary Care Provider's Guide to Diet and Nutrition After Spinal Cord Injury.

Physiological changes that occur after spinal cord injury (SCI) are profound and affect almost every organ system in the human body. Energy balance is significantly altered due to motor paralysis, spasticity or flaccidity, neurogenic sarcopenia, neurogenic osteopenia, sympathetic nervous system disruption, and blunted anabolism. Energy expenditure is markedly reduced, whereas hypothalamic control of appetite and satiety is diminished, resulting in discordant energy intake. Ultimately, neurogenic obesity ensues as the result of a positive energy balance. Even though nutritional guidelines for persons with SCI have been available since 2009, the necessity for body composition assessment and total daily energy expenditure was insufficiently addressed such that most individuals with SCI continued in positive energy balance despite "adherence" to the guidelines. Macronutrients must be carefully assessed to optimize caloric intake, while micronutrient consumption may need to be supplemented in order to meet recommended daily allowances. Such a diet would emphasize foods with low caloric yet high nutrient density. This article reviews current literature regarding nutritional requirements for SCI and provides a straightforward plan for implementing more rigorous dietary interventions meant to address the obesity crisis in this especially vulnerable population.

Berberine attenuated olanzapine-induced metabolic alterations in mice: Targeting transient receptor potential vanilloid type 1 and 3 channels

Transient receptor potential vanilloid type 1 (TRPV1) channels are emerging therapeutic targets for metabolic disorders. Berberine, which is a modulator of TRPV1, has proven antiobesity and antidiabetic potentials. The present study was aimed to investigate the protective effects of berberine in olanzapine-induced alterations in hypothalamic appetite control, inflammation and metabolic aberrations in mice targeting TRPV1 channels. Female BALB/c mice (18–23 g) were treated with olanzapine (6 mg/kg, p.o.) for six weeks to induce metabolic alterations, while berberine (100 and 200 mg/kg, p.o.) and metformin (100 mg/kg, p.o) were used as test and standard interventions respectively. Weekly assessment of feed-water intake, body temperature and body weight was done, while locomotion was measured at the end of week 1 and 6. Serum glucose and lipid profile were assessed by biochemical methods, while other serum biomarkers were assessed by ELISA. qPCR was used to quantify the mRNA expression in the hypothalamus. Olanzapine treatment significantly increased the feed intake, weight gain, adiposity index, while reduced body temperature and locomotor activity which were reversed by berberine treatment. Berberine treatment reduced serum ghrelin and leptin levels as well decrease in hypothalamic mRNA expression of orexigenic neuropeptides, inflammatory markers and ghrelin receptor in olanzapine-treated mice. Olanzapine treatment increased expression of TRPV1/TRPV3 in the hypothalamus which was significantly decreased by berberine treatment. Our results suggest that berberine, by TRPV1/TRPV3 modulation, attenuated the olanzapine-induced metabolic alterations in mice. Hence berberine supplementation in psychiatric patients could be a preventive approach to reduce the metabolic adverse effects of antipsychotics.

Obesity: Hypothalamic Regulation of Food Intake

Current estimates suggest that over 1 billion people are overweight and over 300 million people are obese. Weight gain is due to an imbalance between energy expenditure and dietary intake. This review discusses the hypothalamic control of appetite. Nuclei within the hypothalamus integrate peripheral signals such as adiposity and caloric intake to regulate important pathways within the central nervous system controlling food intake to energy expenditure. These pathways involve the orexigenic NPY/AgRP and the anorexigenic POMC/CART neurons the arcuate nucleus (ARC) of the hypothalamus.

Hypothalamic control of seasonal changes in food intake and body weight.

Seasonal cycles of fattening and body weight reflecting changes in both food intake and energy expenditure are a core aspect of the biology of mammals that have evolved in temperate and arctic latitudes. Identifying the neuroendocrine mechanisms that underlie these cycles has provided new insights into the hypothalamic control of appetite and fuel oxidation. Surprisingly, seasonal cycles do not result from changes in the leptin-responsive and homeostatic pathways located in the mediobasal and lateral hypothalamus that regulate meal timing and compensatory responses to starvation or caloric restriction. Rather, they result from changes in tanycyte function, which locally regulates transport and metabolism of thyroid hormone and retinoic acid. These signals are crucial for the initial development of the brain, so it is hypothesized that seasonal neuroendocrine cycles reflect developmental mechanisms in the adult hypothalamus, manifest as changes in neurogenesis and plasticity of connections.

Exercise training as treatment in cancer cachexia.

Cachexia is a wasting syndrome that may accompany a plethora of diseases, including cancer, chronic obstructive pulmonary disease, aids, and rheumatoid arthritis. It is associated with central and systemic increases of pro-inflammatory factors, and with decreased quality of life, response to pharmacological treatment, and survival. At the moment, there is no single therapy able to reverse cachexia many symptoms, which include disruption of intermediary metabolism, endocrine dysfunction, compromised hypothalamic appetite control, and impaired immune function, among other. Growing evidence, nevertheless, shows that chronic exercise, employed as a tool to counteract systemic inflammation, may represent a low-cost, safe alternative for the prevention/attenuation of cancer cachexia. Despite the well-documented capacity of chronic exercise to counteract sustained disease-related inflammation, few studies address the effect of exercise training in cancer cachexia. The aim of the present review was hence to discuss the results of cachexia treatment with endurance training. As opposed to resistance exercise, endurance exercise may be performed devoid of equipment, is well tolerated by patients, and an anti-inflammatory effect may be observed even at low-intensity. The decrease in inflammatory status induced by endurance protocols is paralleled by recovery of various metabolic pathways. The mechanisms underlying the response to the treatment are considered.

Call for an urgent rethink of the 'health at every size' concept.

Author(s): Amanda Sainsbury[sup.1] and Phillipa Hay[sup.2,3] The argument for an urgent rethink When I (AS) was a child, my grandmother used to say Don't pull an ugly face, because if the wind changes, your face will become stuck like that. I don't know what evidence my grandmother had for this advice, but as a neuroscientist who studies the effects of diet on the hypothalamic control of appetite and body weight, I say Don't eat an ugly diet or let yourself stay fat, because if the wind changes you may become stuck with permanent obesity. The long-term effects of excess calories and adiposity on body weight regulation appear to have been overlooked in the fat acceptance movement that has emerged in parallel with the obesity epidemic. In this commentary I outline the possibility that excess body fat and its underlying contributors lead to permanent changes in the brain pathways that control body weight, and call for urgent reconsideration of the 'health at every size' concept. While I certainly agree that it is possible to have healthy behaviours that provide health benefits at a wide variety of body sizes, I disagree that it is possible to be - or to stay - truly healthy at every size. The World Health Organisation decrees that a body mass index (BMI) of 18.5 to 24.9 kg/m[sup.2] is generally optimum for health, at least for Caucasians between the ages of 18 and 65 [1]. However, there are many people who are healthy who have a BMI outside this range. For instance, some people self-impose long-term calorie restriction and generally have a low BMI and exhibit metabolic benefits, in keeping with animal studies which show that long-term calorie restriction prolongs life [2]. There are also people with a BMI in the overweight ([greater than or equai to] 25 kg/m[sup.2]) or obese ([greater than or equai to] 30 kg/m[sup.2]) range that exhibit no signs of eminent metabolic disease whatsoever, and these are not limited to people who are body builders or elite athletes [3]. Moreover, overweight or obese people who lose as little as 5-10% of their body weight exhibit significant health gains, even if their BMI remains in the overweight or obese range. Examples include improved fertility and pregnancy outcomes [4], moderate to large clinical improvements in osteoarthritic joint pain [5], and a markedly reduced likelihood of progression to type 2 diabetes mellitus [6]. Indeed, without losing any weight at all, substantial health gains can be achieved through better diet and exercise in overweight or obese people [7]. Despite the above evidence that it certainly is possible to be healthy - or to gain health benefits - at a wide variety of BMIs, there is a large body of evidence that having a BMI outside certain limits increase the risk of health problems, hence the WHO recommendations. In general, a low BMI - an indicator of malnutrition - is associated with poor health outcomes. While the exact proportion of obese people who are metabolically healthy varies depending on what criteria are used to define both obesity and health, it is smaller than the proportion of obese people who are not metabolically healthy [3]. As it is currently not possible to predict which people will remain metabolically healthy despite excessive weight gain, it may be dangerous to make blanket community statements that people can have health at every size. Moreover, recent research suggests that even for obese people who are metabolically healthy, it is only a question of time before a variety of issues raise their heads, contributing to significantly greater mortality from cardiovascular disease and all other causes [8]. Whether or not a person with excess weight develops metabolic diseases such as diabetes or cardiovascular disease, sooner or later the mechanical effects of excess weight and the resultant gait abnormalities, combined with systemic inflammation, are likely to take a toll. As one example, adults who are overweight have a 2. …

Sex effects on plasma leptin concentrations in newborn and postnatal beef calves

Changes in neonatal plasma leptin play a central role in regulating development of the hypothalamic appetite control centers in rodents. In lambs, a postnatal leptin surge has just been reported, and maternal obesity induced by overfeeding initiated before conception and continued throughout gestation blocks this leptin surge in newborn lambs. To investigate the presence, timing, and duration of neonatal leptin profiles, nulliparous cows carrying bull (n = 6) and heifer (n = 6) calves were selected. Cows exhibited no complications during parturition and received no assistance during delivery were chosen for this experiment. A blood sample from the jugular vein was obtained within 2 h of birth, then daily until d 8, and then every other day until d 18 of age at 0700 h. Plasma was collected and analyzed for glucose, insulin, cortisol, and leptin concentrations via validated colorimetric and radioimmunoassay procedures. Plasma hormone and metabolite values were analyzed as repeated measures. Bull calves exhibited elevated plasma leptin concentrations compared with heifers (P = 0.01). Furthermore, plasma leptin concentrations increased from birth until d 2 and then decreased until d 16 of age (P < 0.01). Plasma cortisol was elevated (P < 0.01) at birth and then decreased over the next 5 d. Bull calves had greater (P = 0.04) plasma insulin than did heifer calves. We conclude that there is a postnatal change in plasma leptin with differences due to calf sex and may affect the appetite centers of the hypothalamus influencing appetite and BW gain.

Obesity, gut hormones and knighthood

Interview by Rona WilliamsonSteve Bloom was born in Kent in 1942 and received his undergraduate medical training at Cambridge University, Cambridge, UK. His House Officer, Senior House Officer and Registrar posts were undertaken at The Middlesex Hospital where he also received an MRC Clinical Research training Fellowship. He moved to the Royal Postgraduate Medical School at Hammersmith Hospital as a Consultant Physician in 1974 where in due course he became Professor of Medicine. His roles have included Deputy Director of the Department of Medicine, Chairman of the Academic Board, Director of the Endocrinology Clinical Service and, Director of Chemical Pathology (renamed Metabolic Medicine and later Investigative Medicine), Chief of Service for Pathology and Chief of Service for Endocrinology and Diabetes. Having stepped down from his 10-year tenure as Head of Division of Investigative Science in 2007, Steve now holds a dual role within Imperial College London as Head of Division of Diabetes, Endocrinology and Metabolism and Chair of the academic Section of Investigative Medicine and also as Head of Clinical Chemistry at Imperial College Healthcare NHS Trust. His research work over the years falls into five related categories: endocrinology clinical research, physiology and pathology of gut hormones, control of insulin release and insulin resistance, role of neuropeptides in organ control and the role of neuropeptides in CNS regulation of appetite and related hypothalamic functions. He currently leads a research group investigating hypothalamic appetite control systems and gut hormones. This group’s discovery that oxyntomodulin reduces appetite offers a potential new treatment for obesity and in 2005 Steve cofounded spin out company ‘Thiakis Ltd’ to commercialize these findings. In 2008, Wyeth Pharmaceuticals successfully acquired Thiakis for a reported £100 million (milestoned). He has published over 1000 original papers (as well as numerous review articles) in journals such as Nature, J. Biol. Chem., PNAS, JCI and NEJM. In the past Steve has been a member of the Main Scientific Board for AstraZeneca and advisory boards for Upjohn and Novartis. In 2012, Professor Sir Steve Bloom was awarded a Knight Bachelor for Services to medical science.

The Genetics of Anorexia Nervosa

Anorexia nervosa (AN) is a disease defined by inappropriate weight loss and maintenance of body weight <85% of that expected for weight and height; it is most common in adolescent women aged 15-19 years. Numerous studies have highlighted the familial aggregation of the disease, suggesting a significant genetic component to its etiology. The purpose of this review is to discuss the different fields of genetic research--both in humans and animals--that have contributed to the understanding of this complex disorder. Candidate gene studies focusing on genes involved in the hypothalamic control of appetite and energy regulation have found genetic risk variants that increase risk for AN. A recent genome-wide association study has highlighted novel loci for further investigation in AN. Animal models and epigenetic studies are also considered; the most recent advances in each field and their contributions to the understanding of AN are emphasized.

Genetic Association and Gene Expression Analysis IdentifyFGFR1as a New Susceptibility Gene for Human Obesity

Previous studies suggest a role for fibroblast growth factor receptor 1 (FGFR1) in the regulation of energy balance. Our objective was to investigate whether FGFR1 is an obesity gene by genetic association and functional studies. The study was designed to genotype common FGFR1 single-nucleotide polymorphisms (SNP) in large cohorts, confirm significant results in additional cohorts, and measure FGFR1 expression in human adipose tissue and in rodent hypothalamus. General community and referral centers for specialized care was the setting for the study. We genotyped FGFR1 SNP in 2438 obese and 2115 lean adults and 985 obese and 532 population-based children. Results were confirmed in 928 obese and 2738 population-based adults and 487 obese and 441 lean children. Abdominal sc adipose tissue was investigated in 202 subjects. We also investigated diet-induced, obese fasting, and fed rats. We analyzed the association between FGFR1 SNP and obesity. In secondary analyses, we related adipose FGFR1 expression to genotype, obesity, and degree of fat cell differentiation and related hypothalamic FGFR1 to energy balance. FGFR1 rs7012413*T was nominally associated with obesity in all four cohorts; metaanalysis odds ratio = 1.17 (95% confidence interval = 1.10-1.25), and P = 1.8 × 10(-6), which was P = 7.0 × 10(-8) in the recessive model. rs7012413*T was associated with FGFR1 expression in adipose tissue (P < 0.0001). In this organ, but not in skeletal muscle, FGFR1 mRNA (P < 0.0001) and protein (P < 0.05) were increased in obesity. In rats, hypothalamic expression of FGFR1 declined after fasting (P < ]0.001) and increased after diet-induced obesity (P < 0.05). FGFR1 is a novel obesity gene that may promote obesity by influencing adipose tissue and the hypothalamic control of appetite.

Maternal obesity eliminates the neonatal lamb plasma leptin peak

A neonatal peak in rodent plasma leptin plays a central role in regulating development of the hypothalamic appetite control centres. Maternal obesity lengthens and amplifies the peak in altricial rodent species. The precise timing and characteristics of the neonatal leptin peak have not been established in offspring of either normal or obese mothers in any precocial species. We induced obesity by feeding female sheep for 60 days before conception, and throughout pregnancy and parturition with 150% of the diet consumed by control ewes fed to National Research Council recommendations.We have reported that mature offspring of obese sheep fed similarly exhibited increased appetite, weight gain and obesity in response to ad libitum feeding at 19 months of age. We observed a leptin peak in lambs of control ewes between days 6 and 9 of postnatal life, earlier than reported in rodents. This peak was not present in lambs born to obese ewes. The leptin peak in lambs born to control ewes was not clearly related to any changes in plasma cortisol, insulin, triiodothyronine, IGF-1 or glucose. However, there was a significant increase in cortisol at birth in lambs born to obese ewes related to an increase in leptin in the first day of life. We conclude that the increased cortisol seen in lambs of obese sheep plays a role in disrupting the normal peak of leptin in lambs born to obese ewes thereby predisposing them to increased appetite and weight gain in later life.

Mechanisms behind early life nutrition and adult disease outcome.

Obesity is increasing around the globe. While adult lifestyle factors undoubtedly contribute to the incidence of obesity and its attendant disorders, mounting evidence suggests that programming of obesity may occur following under- and over-nutrition during development. As hypothalamic control of appetite and energy expenditure is set early in life and can be perturbed by certain exposures such as undernutrition and altered metabolic and hormonal signals, in utero exposure to altered maternal nutrition and inadequate nutrition during early postnatal life may contribute to programming of obesity in offspring. Data from animal studies indicate both intrauterine and postnatal environments are critical determinants of the development of pathways regulating energy homeostasis. This review summarizes recent evidence of the impact of maternal nutrition as well as postnatal nutrition of the offspring on subsequent obesity and disease risk of the offspring. While much of the experimental work reviewed here was conducted in the rodent, these observations provide useful insights into avenues for future research into developing preventive measures to curb the obesity epidemic.

Early life influences on obesity risk: maternal overnutrition and programming of obesity

While adult lifestyle factors undoubtedly contribute to the incidence of obesity and its attendant disorders, mounting evidence suggests that programming of obesity may occur following over-nutrition during development. As hypothalamic control of appetite and energy expenditure is set early in life and can be perturbed by certain exposures, such as undernutrition and altered metabolic and hormonal signals, in utero exposure to maternal obesity-related changes may contribute to programming of obesity in offspring. Data from animal studies indicate both intrauterine and postnatal environments are critical determinants of the development of pathways regulating energy homeostasis. This review summarizes recent evidence of the impact of maternal obesity on subsequent obesity risk, paying particular attention to the hypothalamic regulation of appetite and markers of metabolic control. The extraordinary rise in the rates of maternal obesity underlines an urgent need to investigate the mechanisms contributing to its transgenerational effects.

Lipopolysaccharide (LPS) stimulates adipokine and socs3 gene expression in mouse brain and pituitary gland in vivo, and in N-1 hypothalamic neurons in vitro

Adipokines that modulate metabolic and inflammatory responses, such as resistin ( rstn) and fasting-induced adipose factor ( fiaf), are also expressed in mouse brain and pituitary gland. Since lipopolysaccharide (LPS)-induced endotoxinemia provokes an anorectic response via a hypothalamic-dependent mechanism we hypothesized that LPS would also modify hypothalamic adipokine expression. Challenging male CD-1 mice with LPS (5 mg/kg; s.c.) significantly reduced bodyweight (24 h) and realtime RT-PCR revealed time- and tissue-dependent increases in rstn, fiaf and suppressor of cytokine signaling-3 ( socs-3) mRNA in hypothalamic, pituitary, cortical and adipose tissues. Gene expression was rapidly increased (3–6 h) in the hypothalamus and pituitary, but returned to normal within 24 h. In contrast, with the exception of rstn in fat, the expression of target genes remained elevated in cortex and visceral fat at 24 h post-injection. In order to more specifically examine the hypothalamic response to LPS we investigated its effects directly on N-1 hypothalamic neurons in vitro. LPS (25 μg/mL; 3 h) had no effect on rstn mRNA, but significantly stimulated fiaf and socs-3 expression. Although various toll-like receptor 4 (TLR4) antagonists (parthenolide, PD098059, and SB202190) did not prevent the LPS-induced increases in fiaf and socs-3, they did partially attenuate its stimulatory effects. We conclude that LPS treatment increases the expression of central, and possibly neuronal, adipokine genes which may influence local tissue repair and function, but could also have downstream consequences on the hypothalamic control of appetite and energy metabolism following an inflammatory insult.