38 results on '"Teppei Fujikawa"'
Search Results
2. CB1Rs in VMH neurons regulate glucose homeostasis but not body weight
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Joel K. Elmquist, Amanda G. Arnold, Madison Granier, Charlotte E. Lee, Jiwon Lee, Teppei Fujikawa, Carlos M. Castorena, Natalie J. Michael, Arely Salazar Tinajero, Alexandre Caron, William L. Holland, Syann Lee, Chelsea Limboy, Newaz Ahmed, Chen Liu, Jay D. Horton, and Simeng Wang
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Male ,0301 basic medicine ,medicine.medical_specialty ,Physiology ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Central nervous system ,Carbohydrate metabolism ,Biology ,Diet, High-Fat ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Receptor, Cannabinoid, CB1 ,CRISPR-Associated Protein 9 ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Homeostasis ,Glucose homeostasis ,Inverse agonist ,Clustered Regularly Interspaced Short Palindromic Repeats ,Obesity ,Receptor ,Gene Editing ,Mice, Knockout ,Neurons ,Body Weight ,Metabolism ,3. Good health ,Mice, Inbred C57BL ,Glucose ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Ventromedial Hypothalamic Nucleus ,Hypothalamus ,Body Composition ,Female ,Cannabinoid ,Energy Metabolism ,030217 neurology & neurosurgery ,Research Article - Abstract
Cannabinoid 1 receptor (CB1R) inverse agonists reduce body weight and improve several parameters of glucose homeostasis. However, these drugs have also been associated with deleterious side effects. CB1R expression is widespread in the brain and in peripheral tissues, but whether specific sites of expression can mediate the beneficial metabolic effects of CB1R drugs, while avoiding the untoward side effects, remains unclear. Evidence suggests inverse agonists may act on key sites within the central nervous system to improve metabolism. The ventromedial hypothalamus (VMH) is a critical node regulating energy balance and glucose homeostasis. To determine the contributions of CB1Rs expressed in VMH neurons in regulating metabolic homeostasis, we generated mice lacking CB1Rs in the VMH. We found that the deletion of CB1Rs in the VMH did not affect body weight in chow- and high-fat diet-fed male and female mice. We also found that deletion of CB1Rs in the VMH did not alter weight loss responses induced by the CB1R inverse agonist SR141716. However, we did find that CB1Rs of the VMH regulate parameters of glucose homeostasis independent of body weight in diet-induced obese male mice. NEW & NOTEWORTHY Cannabinoid 1 receptors (CB1Rs) regulate metabolic homeostasis, and CB1R inverse agonists reduce body weight and improve parameters of glucose metabolism. However, the cell populations expressing CB1Rs that regulate metabolic homeostasis remain unclear. CB1Rs are highly expressed in the ventromedial hypothalamic nucleus (VMH), which is a crucial node that regulates metabolism. With CRISPR/Cas9, we generated mice lacking CB1Rs specifically in VMH neurons and found that CB1Rs in VMH neurons are essential for the regulation of glucose metabolism independent of body weight regulation.
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- 2021
3. CNOT6L regulates hepatokine expression
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Sakie Katsumura, Nadeem Siddiqui, Michael Rock Goldsmith, Jaime H. Cheah, Teppei Fujikawa, Genki Minegishi, Atsushi Yamagata, Yukako Yabuki, Kaoru Kobayashi, Mikako Shirouzu, Takeshi Inagaki, Tim H.-M. Huang, Nicolas Musi, Ivan Topisirovic, Ola Larsson, and Masahiro Morita
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Metabolic Syndrome ,Growth Differentiation Factor 15 ,Physiology ,RNA Stability ,Endocrinology, Diabetes and Metabolism ,Cell Biology ,Article ,Fibroblast Growth Factors ,Eating ,Mice ,Ribonucleases ,Endocrinology ,Liver ,Animals ,Humans ,RNA, Messenger ,Energy Metabolism ,Molecular Biology - Abstract
Hepatokines, secretory proteins from the liver, mediate inter-organ communication to maintain a metabolic balance between food intake and energy expenditure. However, molecular mechanisms by which hepatokine levels are rapidly adjusted following stimuli are largely unknown. Here, we unravel CNOT6L deadenylase switches off hepatokine expression after responding to the stimuli (e.g., exercise and food) to orchestrate energy intake and expenditure. Mechanistically, CNOT6L inhibition stabilizes hepatic Gdf15 and Fgf21 mRNAs, increasing corresponding serum protein levels. The resulting up-regulation of GDF15 stimulates the hindbrain to suppress appetite, while increased FGF21 affects the liver and adipose tissues to induce energy expenditure and lipid consumption. Despite the potential of hepatokines to treat metabolic disorders, their administration therapies have been challenging. Using small-molecule screening, we identified a CNOT6L inhibitor enhancing GDF15 and FGF21 hepatokine levels, which dramatically improves diet-induced metabolic syndrome. Our discovery, therefore, lays the foundation for an unprecedented strategy to treat metabolic syndrome.
- Published
- 2022
4. VMHdm/cSF-1 Neuronal Circuits Regulate Skeletal Muscle PGC1-α via the Sympathoadrenal Drive
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Takuya Yoshida, Scotlynn Farmer, Ami Harada, Zhen Shi, Jenny J. Lee, Arely Tinajero, Ashish K. Singha, and Teppei Fujikawa
- Abstract
To adapt to metabolically challenging environments, the central nervous system (CNS) orchestrates metabolism of peripheral organs including skeletal muscle. The organ-communication between the CNS and skeletal muscle has been investigated, yet our understanding of the neuronal pathway from the CNS to skeletal muscle is still limited. Neurons in the dorsomedial and central parts of the ventromedial hypothalamic nucleus (VMHdm/c) expressing steroidogenic factor-1 (VMHdm/cSF-1 neurons) are key for metabolic adaptations to exercise, including increased basal metabolic rate and skeletal muscle mass in mice. However, the mechanisms by which VMHdm/cSF-1 neurons regulate skeletal muscle function remain unclear. Here, we show that VMHdm/cSF-1 neurons increase the sympathoadrenal activity and regulate skeletal muscle peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) in mice via multiple downstream nodes. Optogenetic activation of VMHdm/cSF-1 neurons dramatically elevates mRNA levels of skeletal muscle Pgc-1α, which regulates a spectrum of skeletal muscle function including protein synthesis and metabolism. Mechanistically, the sympathoadrenal drive coupled with β2 adrenergic receptor (β2AdR) is essential for VMHdm/cSF-1 neurons-mediated increases in skeletal muscle PGC1-α. Specifically, adrenalectomy and knockout of β2AdR block augmented skeletal muscle PGC1-α by VMHdm/cSF-1 neuronal activation. Optogenetic functional mapping reveals that downstream nodes of VMHdm/cSF-1 neurons are functionally redundant to increase circulating epinephrine and skeletal muscle PGC1-α. Collectively, we propose that VMHdm/cSF-1 neurons-skeletal muscle pathway, VMHdm/cSF-1 neurons→multiple downstream nodes→the adrenal gland→skeletal muscle β2AdR, underlies augmented skeletal muscle function for metabolic adaptations.
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- 2022
5. NURR1 activation in skeletal muscle controls systemic energy homeostasis
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Joel K. Elmquist, Leonela Amoasii, Teppei Fujikawa, Eric N. Olson, Rhonda Bassel-Duby, and Efrain Sanchez-Ortiz
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Male ,medicine.medical_specialty ,Transcription, Genetic ,Transgene ,Glucose uptake ,Carbohydrate metabolism ,Energy homeostasis ,Mice ,chemistry.chemical_compound ,Physical Conditioning, Animal ,Internal medicine ,Nuclear Receptor Subfamily 4, Group A, Member 2 ,medicine ,Animals ,Homeostasis ,Humans ,Obesity ,Muscle, Skeletal ,Multidisciplinary ,Glycogen ,business.industry ,Skeletal muscle ,Metabolism ,medicine.disease ,Up-Regulation ,Fatty Liver ,Mice, Inbred C57BL ,Glucose ,medicine.anatomical_structure ,Endocrinology ,PNAS Plus ,Liver ,chemistry ,Hyperglycemia ,Carbohydrate Metabolism ,Steatosis ,Energy Metabolism ,business - Abstract
Skeletal muscle plays a central role in the control of metabolism and exercise tolerance. Analysis of muscle enhancers activated after exercise in mice revealed the orphan nuclear receptor NURR1/NR4A2 as a prominent component of exercise-responsive enhancers. We show that exercise enhances the expression of NURR1, and transgenic overexpression of NURR1 in skeletal muscle enhances physical performance in mice. NURR1 expression in skeletal muscle is also sufficient to prevent hyperglycemia and hepatic steatosis, by enhancing muscle glucose uptake and storage as glycogen. Furthermore, treatment of obese mice with putative NURR1 agonists increases energy expenditure, improves glucose tolerance, and confers a lean phenotype, mimicking the effects of exercise. These findings identify a key role for NURR1 in governance of skeletal muscle glucose metabolism, and reveal a transcriptional link between exercise and metabolism. Our findings also identify NURR1 agonists as possible exercise mimetics with the potential to ameliorate obesity and other metabolic abnormalities.
- Published
- 2019
6. High-Phosphate Diet Induces Exercise Intolerance and Impairs Fatty Acid Metabolism in Mice
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Venkat S. Malladi, James A. Richardson, Ming Chang Hu, Orson W. Moe, Wanpen Vongpatanasin, Philipp E. Scherer, Carlos M. Castorena, Jarett D. Berry, Scott A. Smith, Gary A. Iwamoto, Colby Ayers, Luke I. Szweda, Poghni Peri-Okonny, Jere H. Mitchell, Han-Kyul Kim, John M. Shelton, Teppei Fujikawa, Rhonda Bassel-Duby, and Kedryn K. Baskin
- Subjects
Male ,medicine.medical_specialty ,Preservative ,Exercise intolerance ,030204 cardiovascular system & hematology ,Article ,Cell Line ,Phosphates ,03 medical and health sciences ,chemistry.chemical_compound ,Oxygen Consumption ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,Gene expression ,medicine ,Animals ,Humans ,Muscle, Skeletal ,Enhancer ,Exercise ,Flavor ,030304 developmental biology ,0303 health sciences ,Exercise Tolerance ,Fatty acid metabolism ,business.industry ,Fatty Acids ,Metabolism ,Mitochondria, Muscle ,Mice, Inbred C57BL ,Endocrinology ,Gene Expression Regulation ,chemistry ,Phosphorus, Dietary ,Sedentary Behavior ,medicine.symptom ,Energy Metabolism ,Cardiology and Cardiovascular Medicine ,business ,High phosphate diet - Abstract
Background: Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in the Western diet. Physical inactivity, a common feature of Western societies, is associated with increased cardiovascular morbidity and mortality. It is unknown whether dietary Pi excess contributes to exercise intolerance and physical inactivity. Methods: To determine an association between Pi excess and physical activity in humans, we assessed the relationship between serum Pi and actigraphy-determined physical activity level, as well as left ventricular function by cardiac magnetic resonance imaging, in DHS-2 (Dallas Heart Study phase 2) participants after adjusting for relevant variables. To determine direct effects of dietary Pi on exercise capacity, oxygen uptake, serum nonesterified fatty acid, and glucose were measured during exercise treadmill test in C57/BL6 mice fed either a high-Pi (2%) or normal-Pi (0.6%) diet for 12 weeks. To determine the direct effect of Pi on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in differentiated C2C12 myotubes were conducted after subjecting to media containing 1 to 3 mmol/L Pi (pH 7.0) to simulate in vivo phosphate conditions. Results: In participants of the DHS-2 (n=1603), higher serum Pi was independently associated with reduced time spent in moderate to vigorous physical activity ( P =0.01) and increased sedentary time ( P =0.004). There was no association between serum Pi and left ventricular ejection fraction or volumes. In animal studies, compared with the control diet, consumption of high-Pi diet for 12 weeks did not alter body weight or left ventricular function but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, and fatty acid levels and led to downregulation of genes involved in fatty acid synthesis, release, and oxidation, including Fabp4 , Hsl , Fasn , and Pparγ , in muscle. Similar results were recapitulated in vitro by incubating C2C12 myotubes with high-Pi media. Conclusions: Our data demonstrate a detrimental effect of dietary Pi excess on skeletal muscle fatty acid metabolism and exercise capacity that is independent of obesity and cardiac contractile function. Dietary Pi may represent a novel and modifiable target to reduce physical inactivity associated with the Western diet.
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- 2019
7. Glucose-Lowering by Leptin in the Absence of Insulin Does Not Fully Rely on the Central Melanocortin System in Male Mice
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Newaz Ahmed, Junya Yamaguchi, Ashish Kumar Singha, Nancy S Gonzalez, Teppei Fujikawa, and Glenn M. Toney
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Blood Glucose ,Leptin ,Male ,0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Blood sugar ,030209 endocrinology & metabolism ,Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Central melanocortin system ,Internal medicine ,medicine ,Animals ,Insulin ,Receptor ,Research Articles ,Leptin receptor ,digestive, oral, and skin physiology ,Arcuate Nucleus of Hypothalamus ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,SIM1 ,Receptor, Melanocortin, Type 4 ,Receptors, Leptin ,Melanocortin ,hormones, hormone substitutes, and hormone antagonists ,Paraventricular Hypothalamic Nucleus - Abstract
Central leptin administration can ameliorate hyperglycemia in insulin-deficient rodent models independently of insulin; however, the underlying neuronal mechanism are unclear. Here, we investigate the contribution of key elements within the central melanocortin system by examining whether central leptin injection can ameliorate hyperglycemia in total insulin-deficient mice that either lacked melanocortin 4 receptors (MC4Rs) in the whole body [knockout (KO); MC4R KO] or selectively, in single-minded homolog 1 (SIM1)–expressing neurons (SIM1(ΔMC4R)). We further investigated the contribution of leptin receptors (LEPRs) in agouti-related protein (AgRP)–expressing neurons (AgRP(∆LEPR)). Leptin injections into the cerebral ventricle attenuated mortality and elevated blood glucose in total insulin-deficient MC4R KO mice. Total insulin-deficient SIM1(ΔMC4R) mice exhibited the same magnitude reduction of blood glucose in response to leptin injections as MC4R KO mice, suggesting SIM1 neurons are key to MC4R-mediated, insulin-independent, glucose-lowering effects of leptin. Central leptin injection also partially rescued glucose levels in total insulin-deficient AgRP(∆LEPR) mice. In brain slice studies, basal discharge of AgRP neurons from mice with total insulin deficiency was increased and leptin partially reduced their firing rate without membrane potential hyperpolarization. Collectively, our findings indicate that, contrary to glucose-lowering effects of leptin in the presence of insulin or partial insulin deficiency, MC4Rs in SIM1 neurons and LEPRs in AgRP neurons are not solely responsible for glucose-lowering effects of leptin in total insulin deficiency. This indicates that the central melanocortin system operates with other neuronal systems to fully mediate glucose-lowering effects of leptin in an insulin-independent manner.
- Published
- 2019
8. Central regulation of glucose metabolism in an insulin‐dependent and ‐independent manner
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Teppei Fujikawa
- Subjects
Leptin ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Central nervous system ,Hypothalamus ,030209 endocrinology & metabolism ,Carbohydrate metabolism ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Homeostasis ,Humans ,Insulin ,Glucose homeostasis ,Neurons ,Endocrine and Autonomic Systems ,business.industry ,Lipid metabolism ,medicine.disease ,Glucose ,medicine.anatomical_structure ,Energy Metabolism ,business ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
The central nervous system (CNS) contributes significantly to glucose homeostasis. The available evidence indicates that insulin directly acts on the CNS, in particular the hypothalamus, to regulate hepatic glucose production, thereby controlling whole-body glucose metabolism. Additionally, insulin also acts on the brain to regulate food intake and fat metabolism, which may indirectly regulate glucose metabolism. Studies conducted over the last decade have found that the CNS can regulate glucose metabolism in an insulin-independent manner. Enhancement of central leptin signalling reverses hyperglycaemia in insulin-deficient rodents. Here, I review the mechanisms by which central insulin and leptin actions regulate glucose metabolism. Although clinical studies have shown that insulin treatment is currently indispensable for managing diabetes, unravelling the neuronal mechanisms underlying the central regulation of glucose metabolism will pave the way for the design of novel therapeutic drugs for diabetes.
- Published
- 2021
9. Author response for 'Central regulation of glucose metabolism in an insulin‐dependent and ‐independent manner'
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Teppei Fujikawa
- Subjects
medicine.medical_specialty ,Endocrinology ,Chemistry ,Internal medicine ,medicine ,Carbohydrate metabolism ,Insulin dependent - Published
- 2021
10. Review for 'Central signalling cross-talk between insulin and leptin in glucose and energy homeostasis'
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Teppei Fujikawa
- Subjects
medicine.medical_specialty ,Endocrinology ,Signalling ,Leptin ,Insulin ,medicine.medical_treatment ,Internal medicine ,medicine ,Biology ,Energy homeostasis - Published
- 2020
11. Leptin Receptors in RIP-Cre25Mgn Neurons Mediate Anti-dyslipidemia Effects of Leptin in Insulin-Deficient Mice
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Ashish Singha, Juan Pablo Palavicini, Meixia Pan, Scotlynn Farmer, Darleen Sandoval, Xianlin Han, and Teppei Fujikawa
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0301 basic medicine ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,glucose metabolism ,Adipose tissue ,030209 endocrinology & metabolism ,Carbohydrate metabolism ,Biology ,leptin ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,lipid metabolism ,medicine ,insulin deficiency ,Leptin receptor ,lcsh:RC648-665 ,Insulin ,Leptin ,nutritional and metabolic diseases ,Lipid metabolism ,the hypothalamus ,medicine.disease ,030104 developmental biology ,Endocrinology ,Dyslipidemia ,hormones, hormone substitutes, and hormone antagonists ,Hormone - Abstract
Leptin is a potent endocrine hormone produced by adipose tissue and regulates a broad range of whole-body metabolism such as glucose and lipid metabolism, even without insulin. Central leptin signaling can lower hyperglycemia in insulin-deficient rodents via multiple mechanisms, including improvements of dyslipidemia. However, the specific neurons that regulate anti-dyslipidemia effects of leptin remain unidentified. Here we report that leptin receptors (LEPRs) in neurons expressing Cre recombinase driven by a short fragment of a promoter region of Ins2 gene (RIP-Cre25Mgn neurons) are required for central leptin signaling to reverse dyslipidemia, thereby hyperglycemia in insulin-deficient mice. Ablation of LEPRs in RIP-Cre25Mgn neurons completely blocks glucose-lowering effects of leptin in insulin-deficient mice. Further investigations reveal that insulin-deficient mice lacking LEPRs in RIP-Cre25Mgn neurons (RIP-CreΔLEPR mice) exhibit greater lipid levels in blood and liver compared to wild-type controls, and that leptin injection into the brain does not suppress dyslipidemia in insulin-deficient RIP-CreΔLEPR mice. Leptin administration into the brain combined with acipimox, which lowers blood lipids by suppressing triglyceride lipase activity, can restore normal glycemia in insulin-deficient RIP-CreΔLEPR mice, suggesting that excess circulating lipids are a driving-force of hyperglycemia in these mice. Collectively, our data demonstrate that LEPRs in RIP-Cre25Mgn neurons significantly contribute to glucose-lowering effects of leptin in an insulin-independent manner by improving dyslipidemia.
- Published
- 2020
12. Leptin Receptors in RIP-Cre
- Author
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Ashish, Singha, Juan Pablo, Palavicini, Meixia, Pan, Scotlynn, Farmer, Darleen, Sandoval, Xianlin, Han, and Teppei, Fujikawa
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Leptin ,Male ,Neurons ,endocrine system diseases ,Integrases ,glucose metabolism ,nutritional and metabolic diseases ,Mice, Transgenic ,the hypothalamus ,Mice ,Glucose ,Endocrinology ,Hyperglycemia ,lipid metabolism ,Animals ,Insulin ,Receptors, Leptin ,insulin deficiency ,hormones, hormone substitutes, and hormone antagonists ,Dyslipidemias ,Original Research - Abstract
Leptin is a potent endocrine hormone produced by adipose tissue and regulates a broad range of whole-body metabolism such as glucose and lipid metabolism, even without insulin. Central leptin signaling can lower hyperglycemia in insulin-deficient rodents via multiple mechanisms, including improvements of dyslipidemia. However, the specific neurons that regulate anti-dyslipidemia effects of leptin remain unidentified. Here we report that leptin receptors (LEPRs) in neurons expressing Cre recombinase driven by a short fragment of a promoter region of Ins2 gene (RIP-Cre25Mgn neurons) are required for central leptin signaling to reverse dyslipidemia, thereby hyperglycemia in insulin-deficient mice. Ablation of LEPRs in RIP-Cre25Mgn neurons completely blocks glucose-lowering effects of leptin in insulin-deficient mice. Further investigations reveal that insulin-deficient mice lacking LEPRs in RIP-Cre25Mgn neurons (RIP-CreΔLEPR mice) exhibit greater lipid levels in blood and liver compared to wild-type controls, and that leptin injection into the brain does not suppress dyslipidemia in insulin-deficient RIP-CreΔLEPR mice. Leptin administration into the brain combined with acipimox, which lowers blood lipids by suppressing triglyceride lipase activity, can restore normal glycemia in insulin-deficient RIP-CreΔLEPR mice, suggesting that excess circulating lipids are a driving-force of hyperglycemia in these mice. Collectively, our data demonstrate that LEPRs in RIP-Cre25Mgn neurons significantly contribute to glucose-lowering effects of leptin in an insulin-independent manner by improving dyslipidemia.
- Published
- 2020
13. Leptin Receptors in RIP-Cre25Mgnneurons Mediate Anti-Dyslipidemia Effects of Leptin in Insulin-Deficient Male Mice
- Author
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Darleen A. Sandoval, Ashish Kumar Singha, Teppei Fujikawa, Juan Pablo Palavicini, Meixia Pan, and Xianlin Han
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endocrine system ,0303 health sciences ,medicine.medical_specialty ,Acipimox ,Leptin receptor ,endocrine system diseases ,Leptin ,Insulin ,medicine.medical_treatment ,nutritional and metabolic diseases ,Adipose tissue ,Lipid metabolism ,Biology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,Dyslipidemia ,030304 developmental biology ,medicine.drug ,Hormone - Abstract
Leptin is a potent endocrine hormone produced by adipose tissue and regulates a broad range of metabolism including glucose and lipid metabolism, with and without insulin. It is evident that central leptin signaling can lower hyperglycemia in insulin-deficient rodents via multiple mechanisms including restoration of dyslipidemia. However, the specific neurons that regulate these glucose-lowering and anti-dyslipidemia effects of leptin remain unidentified. Here we report that leptin receptors (LEPRs) in neurons expressing Cre recombinase driven by a short fragment of a promoter region ofIns2gene (RIP-Cre25Mgnneurons) are required for central leptin signaling to reverse hyperglycemia and dyslipidemia in insulin-deficient mice. Ablation of LEPRs in RIP-Cre25Mgnneurons completely blocks glucose-lowering effects of leptin in insulin-deficient mice. Further investigations reveal that insulin-deficient mice lacking LEPRs in RIP-Cre25Mgnneurons (RIP-CreΔLEPRmice) exhibit greater lipid levels in blood and liver compared to wild-type controls, and that leptin injection into the brain does not suppress dyslipidemia in insulin-deficient RIP-CreΔLEPRmice. Leptin administration into the brain combined with acipimox, which lowers blood lipids by suppressing triglyceride lipase activity, can restore normal glycemia in insulin-deficient RIP-CreΔLEPRmice, suggesting that excess circulating lipids are a driving-force of hyperglycemia in insulin-deficient RIP-CreΔLEPRmice. Collectively, our data demonstrate that LEPRs in RIP-Cre25Mgnneurons significantly contribute to glucose-lowering effects of leptin in an insulin-independent manner by suppression of dyslipidemia.
- Published
- 2020
14. P110β in the ventromedial hypothalamus regulates glucose and energy metabolism
- Author
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Jose Donato, Charlotte E. Lee, Ki Woo Kim, Syann Lee, Carol F. Elias, Dong Min Shin, Yun Hee Choi, Dong Joo Yang, Teppei Fujikawa, and Daisuke Kohno
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Clinical Biochemistry ,Hypothalamus ,lcsh:Medicine ,Adipose tissue ,Carbohydrate metabolism ,Steroidogenic Factor 1 ,Biochemistry ,Energy homeostasis ,Article ,lcsh:Biochemistry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,lcsh:QD415-436 ,Obesity ,Molecular Biology ,PI3K/AKT/mTOR pathway ,In Situ Hybridization ,Mice, Knockout ,Chemistry ,Insulin ,Leptin ,lcsh:R ,Metabolism ,Cell biology ,Experimental models of disease ,030104 developmental biology ,Glucose ,030220 oncology & carcinogenesis ,Molecular Medicine ,Energy Metabolism ,Neuroscience - Abstract
Phosphoinositide 3-kinase (PI3K) signaling in hypothalamic neurons integrates peripheral metabolic cues, including leptin and insulin, to coordinate systemic glucose and energy homeostasis. PI3K is composed of different subunits, each of which has several unique isoforms. However, the role of the PI3K subunits and isoforms in the ventromedial hypothalamus (VMH), a prominent site for the regulation of glucose and energy homeostasis, is unclear. Here we investigated the role of subunit p110β in steroidogenic factor-1 (SF-1) neurons of the VMH in the regulation of metabolism. Our data demonstrate that the deletion of p110β in SF-1 neurons disrupts glucose metabolism, rendering the mice insulin resistant. In addition, the deletion of p110β in SF-1 neurons leads to the whitening of brown adipose tissues and increased susceptibility to diet-induced obesity due to blunted energy expenditure. These results highlight a critical role for p110β in the regulation of glucose and energy homeostasis via VMH neurons., Metabolism: Enzymatic subunit essential to brain’s glucose responses A particular subunit of a critical signaling enzyme is needed for neurons inside the brain’s hypothalamus to properly regulate energy metabolism. Ki Woo Kim from Yonsei University College of Dentistry, Seoul, South Korea, and colleagues explored the role that the PI3K enzyme plays in neurons of the ventromedial area toward the front of the hypothalamus, a region involved in regulating hunger and metabolism. Deleting a subunit of PI3K called p110β, which is needed for enzymatic function, made mice less responsive to insulin, the hormone that keeps blood sugar levels at healthy levels. As well as having abnormal glucose metabolism, the mice converted more brown fat, which burns energy, into white fat, which stores energy. They were also more susceptible to diet-induced obesity. The findings point toward p110β as a potential drug target for treating diabetes.
- Published
- 2019
15. High Phosphate Diet Induces Exercise Intolerance and Impairs Fatty Acid Metabolism in Mice
- Author
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Orson W. Moe, Ming Chang Hu, Luke I. Szweda, Poghni Peri-Okonny, Colby Ayers, Jere H. Mitchell, Han Kyul Allen Kim, Rhonda Bassel-Duby, Wanpen Vongpatanasin, John M. Shelton, Teppei Fujikawa, Scott A. Smith, Phillip E Scherer, Carlos M. Castro, Jarett D. Berry, Kedryn K. Baskin, Venkat S. Malladi, James A. Richardson, and Gary A. Iwamoto
- Subjects
medicine.medical_specialty ,Fatty acid metabolism ,Chemistry ,Exercise intolerance ,Biochemistry ,chemistry.chemical_compound ,Endocrinology ,Internal medicine ,Genetics ,medicine ,medicine.symptom ,Molecular Biology ,High phosphate diet ,Biotechnology - Published
- 2019
16. Author response: POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels
- Author
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Carlos M. Castorena, Joel K. Elmquist, Newaz Ahmed, Caleb C. Lord, Heather M Dungan Lemko, William L. Holland, Alexandre Caron, Syann Lee, Teppei Fujikawa, Chen Liu, and Charlotte E. Lee
- Subjects
medicine.medical_specialty ,Leptin receptor ,Endocrinology ,Internal medicine ,Leptin ,medicine ,Biology - Published
- 2018
17. POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels
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Carlos M. Castorena, Heather M Dungan Lemko, Alexandre Caron, Syann Lee, Newaz Ahmed, Chen Liu, Charlotte E. Lee, Caleb C. Lord, Joel K. Elmquist, William L. Holland, and Teppei Fujikawa
- Subjects
0301 basic medicine ,Food intake ,Sympathetic nervous system ,Pro-Opiomelanocortin ,Sympathetic Nervous System ,Mouse ,Glucose homeostasis ,Eating ,Mice ,Homeostasis ,Biology (General) ,Neurons ,General Neuroscience ,Leptin ,digestive, oral, and skin physiology ,POMC ,General Medicine ,medicine.anatomical_structure ,Receptors, Leptin ,Medicine ,hormones, hormone substitutes, and hormone antagonists ,Research Article ,medicine.medical_specialty ,Adrenergic receptor ,fasting ,QH301-705.5 ,Science ,Biology ,Inhibitory postsynaptic potential ,ADRA2A ,leptin ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Receptors, Adrenergic, alpha-2 ,Internal medicine ,medicine ,Animals ,Humans ,Secretion ,Human Biology and Medicine ,Leptin receptor ,General Immunology and Microbiology ,030104 developmental biology ,Endocrinology ,Glucose ,nervous system ,Energy Metabolism ,Neuroscience - Abstract
Leptin is critical for energy balance, glucose homeostasis, and for metabolic and neuroendocrine adaptations to starvation. A prevalent model predicts that leptin’s actions are mediated through pro-opiomelanocortin (POMC) neurons that express leptin receptors (LEPRs). However, previous studies have used prenatal genetic manipulations, which may be subject to developmental compensation. Here, we tested the direct contribution of POMC neurons expressing LEPRs in regulating energy balance, glucose homeostasis and leptin secretion during fasting using a spatiotemporally controlledLeprexpression mouse model. We report a dissociation between leptin’s effects on glucose homeostasis versus energy balance in POMC neurons. We show that these neurons are dispensable for regulating food intake, but are required for coordinating hepatic glucose production and for the fasting-induced fall in leptin levels, independent of changes in fat mass. We also identify a role for sympathetic nervous system regulation of the inhibitory adrenergic receptor (ADRA2A) in regulating leptin production. Collectively, our findings highlight a previously unrecognized role of POMC neurons in regulating leptin levels.
- Published
- 2018
18. The hypothalamic regulation of metabolic adaptations to exercise
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Teppei Fujikawa, Carlos M. Castorena, Syann Lee, and Joel K. Elmquist
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0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Central nervous system ,Physical activity ,Disease ,Article ,Nutrient density ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Physical Conditioning, Animal ,medicine ,Animals ,Humans ,Obesity ,Exercise ,Sedentary lifestyle ,Endocrine and Autonomic Systems ,business.industry ,medicine.disease ,Adaptation, Physiological ,030104 developmental biology ,medicine.anatomical_structure ,Hypothalamus ,Ventromedial Hypothalamic Nucleus ,business ,Energy Metabolism ,030217 neurology & neurosurgery - Abstract
Our modern lifestyle is characterised by easy access to nutrient dense foods combined with limited physical activity. A sedentary lifestyle is one of several factors that have contributed to the global obesity epidemic and it also predisposes to chronic illnesses such as diabetes and cardiovascular disease. Although many studies have focused on the benefits of exercise in peripheral tissues, the contributions of the central nervous system to these exercise-induced metabolic adaptations are relatively unknown. The present review highlights the role of the ventromedial hypothalamus in regulating the metabolic response to exercise.
- Published
- 2017
19. Hypothalamic-mediated control of glucose balance in the presence and absence of insulin
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Teppei Fujikawa and Roberto Coppari
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Leptin ,insulin ,Aging ,medicine.medical_specialty ,medicine.medical_treatment ,Hypothalamus ,Disease ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Diabetes mellitus ,Diabetes Mellitus ,medicine ,Animals ,Humans ,030304 developmental biology ,0303 health sciences ,Type 1 diabetes ,business.industry ,Insulin ,Diabetes ,Type 2 Diabetes Mellitus ,Cell Biology ,medicine.disease ,3. Good health ,Glucose ,Endocrinology ,Research Perspective ,Life expectancy ,business ,030217 neurology & neurosurgery ,Hormone - Abstract
Diabetes afflicts hundreds of millions worldwide. People affected by type 1 diabetes mellitus (T1DM; the insulin-deficient form of diabetes) or type 2 diabetes mellitus (T2DM; the insulin-resistant form of diabetes) have significantly reduced life expectancy compared to normal individuals. This is due in part to the fact that (despite improvements) current anti-diabetic approaches are suboptimal. Indeed, severe morbidities (e.g.: cardiovascular disease, hypertension) are still too often associated with diabetes. Recent preclinical results indicate that different types of hypothalamic neurons are endowed with the ability to mediate the hyperglycemia-lowering action of the adipocyte-derived hormone leptin in an insulin-dependent and insulin-independent fashion. These results may pave the way for better anti-diabetic approaches and therefore positively impact on life expectancy of diabetic subjects.
- Published
- 2014
20. Author response: SF-1 expression in the hypothalamus is required for beneficial metabolic effects of exercise
- Author
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Carlos M. Castorena, Joel K. Elmquist, Pavan K. Battiprolu, Philipp E. Scherer, Newaz Ahmed, Joseph A. Hill, William L. Holland, Christine M. Kusminski, Teppei Fujikawa, Mackenzie J. Pearson, Ki Woo Kim, and Syann Lee
- Subjects
030110 physiology ,0301 basic medicine ,03 medical and health sciences ,medicine.medical_specialty ,Endocrinology ,Expression (architecture) ,Hypothalamus ,Internal medicine ,Metabolic effects ,medicine ,Biology - Published
- 2016
21. Blood Lactate Functions as a Signal for Enhancing Fatty Acid Metabolism during Exercise via TGF-^|^beta; in the Brain
- Author
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Ryo Kitaoka, Tohru Fushiki, Hiroyuki Yamada, Kazuo Inoue, Tetsuro Shibakusa, Teppei Fujikawa, Yoko Iwaki, Mina Fujitani, and Shigenobu Matsumura
- Subjects
medicine.medical_specialty ,Nutrition and Dietetics ,Fatty acid metabolism ,business.industry ,Medicine (miscellaneous) ,SMA ,chemistry.chemical_compound ,Cerebrospinal fluid ,Endocrinology ,Biochemistry ,chemistry ,Internal medicine ,Medicine ,Signal transduction ,Treadmill ,business ,Respiratory exchange ratio ,Beta oxidation ,Transforming growth factor - Abstract
Moderate-intensity running (treadmill velocity of 21 m/min) increased blood lactate and actived transforming growth factor-β (TGF-β) concentration in rat cerebrospinal fluid (CSF). On the other hand, low-intensity running (15 m/min) did not increase blood lactate and caused no change in CSF TGF-β. Intraperitoneal (i.p.) administration of lactate to anesthetized rats caused an increase in blood lactate similar to that observed after a 21 m/min running exercise and increased the level of active TGF-β in CSF. Intraperitoneal administration of lactate at the same dose to awake and unrestricted rats caused a decrease in the respiratory exchange ratio, that is, enhancement of fatty acid oxidation and depression of spontaneous motor activity (SMA). Given that intracisternal administration of TGF-β to rats has been reported to enhance fatty acid metabolism and to depress SMA, we surmise that the observed changes caused by i.p. lactate administration in this study were mediated, at least in part, by TGF-β in the brain.
- Published
- 2012
22. Inhibition of fatty acid oxidation activates transforming growth factor-beta in cerebrospinal fluid and decreases spontaneous motor activity
- Author
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Ryo Fujita, Shigenobu Matsumura, Yoko Iwaki, Tohru Fushiki, Kazuo Inoue, and Teppei Fujikawa
- Subjects
Male ,medicine.medical_specialty ,medicine.medical_treatment ,Experimental and Cognitive Psychology ,Deoxyglucose ,Motor Activity ,Carbohydrate metabolism ,Vagotomy ,Rats, Sprague-Dawley ,Behavioral Neuroscience ,Cerebrospinal fluid ,Transforming Growth Factor beta ,Physical Conditioning, Animal ,Internal medicine ,medicine ,Animals ,Homeostasis ,TGF-beta ,Enzyme Inhibitors ,Beta oxidation ,Exercise ,Mercaptoacetate ,Analysis of Variance ,biology ,Chemistry ,Fatty Acids ,Vagus Nerve ,Transforming growth factor beta ,SMA ,Rats ,Vagus nerve ,Endocrinology ,2-deoxyglucose ,Thioglycolates ,Fatty acid oxidation ,biology.protein ,Energy Metabolism ,Oxidation-Reduction ,Transforming growth factor - Abstract
We have previously reported that transforming growth factor (TGF)-beta in the cerebrospinal fluid (CSF) is involved in the mechanism underlying the regulation of spontaneous motor activity (SMA) by the central nervous system after exercise. However, it remained unclear what physiological condition triggers the activation of TGF-beta. We hypothesized that the shortage of energy derived from fatty acid (FA) oxidation observed in the early phase of exercise activated TGF-beta in the CSF. To test this hypothesis, we investigated whether mercaptoacetate (MA), an inhibitor of FA oxidation, could induce an activation of TGF-beta in the CSF and a decrease in SMA. Intraperitoneal (i.p.) administration of MA activated TGF-beta in CSF in rats and depressed SMA; 2-deoxyglucose, an inhibitor of carbohydrate oxidation, on the other hand, depressed SMA but failed to activate CSF TGF-beta. Intracisternal administration of anti-TGF-beta antibody abolished the depressive effect of MA on SMA. We also found that the depression of SMA and the activation of TGF-beta in the CSF by i.p. MA administration were eliminated by vagotomy. Our data suggest that TGF-beta in the CSF is activated by the inhibition of FA oxidation via the vagus nerve and that this subsequently induces depression of SMA.
- Published
- 2010
23. SIRT1 Deacetylase in POMC Neurons Is Required for Homeostatic Defenses against Diet-Induced Obesity
- Author
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Mario Perello, Teppei Fujikawa, Giorgio Ramadori, Jason G. Anderson, Claudia R. Vianna, Raul Mostoslavsky, Ronald C. Stuart, Donald A. Morgan, Roberto Coppari, Kamal Rahmouni, Eduardo A. Nillni, and Makoto Fukuda
- Subjects
Leptin ,medicine.medical_specialty ,Pro-Opiomelanocortin ,Physiology ,Adipose Tissue, White ,HUMDISEASE ,White adipose tissue ,Nicotinamide adenine dinucleotide ,MOLNEURO ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Sirtuin 1 ,Internal medicine ,medicine ,Animals ,Homeostasis ,Obesity ,Molecular Biology ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Neurons ,0303 health sciences ,biology ,Cell Biology ,Dietary Fats ,Endocrinology ,chemistry ,nervous system ,biology.protein ,Female ,NAD+ kinase ,Signal transduction ,Energy Metabolism ,030217 neurology & neurosurgery ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction - Abstract
Summary Feeding on high-calorie (HC) diets induces serious metabolic imbalances, including obesity. Understanding the mechanisms against excessive body weight gain is critical for developing effective antiobesity strategies. Here we show that lack of nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase SIRT1 in pro-opiomelanocortin (POMC) neurons causes hypersensitivity to diet-induced obesity due to reduced energy expenditure. The ability of leptin to properly engage the phosphoinositide 3-kinase (PI3K) signaling in POMC neurons and elicit remodeling of perigonadal white adipose tissue (WAT) is severely compromised in mutant mice. Also, electrophysiological and histomorphomolecular analyses indicate a selective reduction in sympathetic nerve activity and brown-fat-like characteristics in perigonadal WAT of mutant mice, suggesting a physiologically important role for POMC neurons in controlling this visceral fat depot. In summary, our results provide direct genetic evidence that SIRT1 in POMC neurons is required for normal autonomic adaptations against diet-induced obesity.
- Published
- 2010
- Full Text
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24. Increased Noradrenergic Activity in the Ventromedial Hypothalamus during Treadmill Running in Rats
- Author
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Takashi Miyaki, Kazuo Inoue, Ryo Kitaoka, Tohru Fushiki, Shigenobu Matsumura, and Teppei Fujikawa
- Subjects
Male ,Serotonin ,Sympathetic nervous system ,Microdialysis ,medicine.medical_specialty ,Time Factors ,Dopamine ,Medicine (miscellaneous) ,Physical exercise ,Fatty Acids, Nonesterified ,Motor Activity ,Rats, Sprague-Dawley ,Norepinephrine ,Random Allocation ,Oxygen Consumption ,Internal medicine ,medicine ,Animals ,Neurons ,Nutrition and Dietetics ,3-Hydroxybutyric Acid ,Pulmonary Gas Exchange ,Chemistry ,Dopaminergic ,Lipid Metabolism ,Rats ,Up-Regulation ,medicine.anatomical_structure ,Endocrinology ,Ventromedial Hypothalamic Nucleus ,Hypothalamus ,Catecholamine ,Exercise intensity ,Carbohydrate Metabolism ,Corticosterone ,Energy Metabolism ,medicine.drug - Abstract
Physical exercise dramatically increases the energy expenditure of animals. In terms of energy substrate, at the onset of exercise, the contribution of carbohydrates to the energy expenditure is relatively predominant, and decreases gradually with the progression of exercise, while fat consumption increases progressively. The ventromedial hypothalamus (VMH) is a nucleus in the hypothalamus that regulates whole body energy metabolism via the sympathetic nervous system. Some reports have indicated that noradrenergic projections to the VMH are involved in energy metabolism during exercise. However, it is not clear whether exercise influences the activity of noradrenergic projections to the VMH. We hypothesize that during exercise, noradrenergic neurons projecting to the VMH are activated, and play an important part in enhancing fat oxidation. To test this hypothesis, we used in vivo microdialysis to investigate the effect of exercise on the activity of monoaminergic (noradrenaline: NA, dopamine: DA, serotonin: 5-HT) neurons projecting to the VMH of rats. Rats were subjected to running at 15 m/min (incline 3 degrees) for 60 min. During treadmill running, noradrenergic and dopaminergic activities increased significantly in the VMH. Extracellular 5-HT concentrations in the VMH did not change during treadmill running at the exercise intensity. Given the known effects of NA in the VMH on energy metabolism, our results suggest that the increase in noradrenergic activity in the VMH is related to the enhancement of fat oxidation during exercise.
- Published
- 2010
25. Central Administration of Resveratrol Improves Diet-Induced Diabetes
- Author
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Claudia R. Vianna, Laurent Gautron, Giorgio Ramadori, Roberto Coppari, Joel K. Elmquist, and Teppei Fujikawa
- Subjects
Male ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Blotting, Western ,Clinical Biochemistry ,Type 2 diabetes ,Protein Serine-Threonine Kinases ,Resveratrol ,Biology ,Biochemistry ,Antioxidants ,Article ,Eating ,Mice ,chemistry.chemical_compound ,Endocrinology ,Sirtuin 1 ,Internal medicine ,Diabetes mellitus ,Stilbenes ,medicine ,Hyperinsulinemia ,Animals ,Homeostasis ,Reverse Transcriptase Polymerase Chain Reaction ,Leptin ,Insulin ,Body Weight ,Biochemistry (medical) ,NF-kappa B ,food and beverages ,Brain ,medicine.disease ,Dietary Fats ,Mice, Inbred C57BL ,Glucose ,Diabetes Mellitus, Type 2 ,Liver ,chemistry ,Hyperglycemia ,Signal transduction ,hormones, hormone substitutes, and hormone antagonists - Abstract
Resveratrol is a natural polyphenolic compound that activates nicotinamide adenosine dinucleotide-dependent deacetylase SIRT1. Resveratrol has recently been shown to exert potent antidiabetic actions when orally delivered to animal models of type 2 diabetes. However, the tissue(s) mediating these beneficial effects is unknown. Because SIRT1 is expressed in central nervous system (CNS) neurons known to control glucose and insulin homeostasis, we hypothesized that resveratrol antidiabetic effects are mediated by the brain. Here, we report that long-term intracerebroventricular infusion of resveratrol normalizes hyperglycemia and greatly improves hyperinsulinemia in diet-induced obese and diabetic mice. It is noteworthy that these effects are independent of changes in body weight, food intake, and circulating leptin levels. In addition, CNS resveratrol delivery improves hypothalamic nuclear factor-κB inflammatory signaling by reducing acetylated-RelA/p65 and total RelA/p65 protein contents, and inhibitor of nuclear factor-κB α and IκB kinase β mRNA levels. Furthermore, this treatment leads to reduced hepatic phosphoenolpyruvate carboxykinase 1 mRNA and protein levels and ameliorates pyruvate-induced hyperglycemia in this mouse model of type 2 diabetes. Collectively, our results unveiled a previously unrecognized key role for the CNS in mediating the antidiabetic actions of resveratrol.
- Published
- 2009
26. Transforming growth factor-beta in the brain enhances fat oxidation via noradrenergic neurons in the ventromedial and paraventricular hypothalamic nucleus
- Author
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Tohru Fushiki, Kazuo Inoue, Shigenobu Matsumura, Hiroyuki Yamada, and Teppei Fujikawa
- Subjects
Male ,medicine.medical_specialty ,Microdialysis ,Central nervous system ,Fats ,Rats, Sprague-Dawley ,Lesion ,Norepinephrine ,Transforming Growth Factor beta3 ,Internal medicine ,medicine ,Extracellular ,Animals ,Neurotoxin ,Oxidopamine ,Molecular Biology ,Microinjection ,Brain Chemistry ,Neurons ,Analysis of Variance ,biology ,General Neuroscience ,Body Weight ,Transforming growth factor beta ,Rats ,Endocrinology ,medicine.anatomical_structure ,Ventromedial Hypothalamic Nucleus ,Hypothalamus ,biology.protein ,Neurology (clinical) ,medicine.symptom ,Energy Metabolism ,Oxidation-Reduction ,Paraventricular Hypothalamic Nucleus ,Developmental Biology - Abstract
We have previously reported that intracisternal administration of TGF-beta induces an increase in fat oxidation and that intracisternal administration of anti-TGF-beta antibody partially inhibits an increase in fat oxidation during treadmill running in rats. These results indicate a regulatory role of that TGF-beta in the brain on fat oxidation during exercise. However, it is not clear how TGF-beta in the brain enhance fat oxidation. We hypothesized that TGF-beta in the brain elicits its regulatory effects on fat oxidation via hypothalamic noradrenergic neurons, because some reports have demonstrated the important role of hypothalamic noradrenergic neurons in the regulation of fat oxidation during and after exercise. To examine this hypothesis, we measured the extracellular noradrenaline (NA) levels in the paraventricular hypothalamic nucleus (PVH), ventromedial hypothalamic nucleus (VMH) and lateral hypothalamic area, which are especially important in the regulation of energy metabolism, after intracisternal administration of TGF-beta by using an in vivo brain microdialysis. Microdialysis study revealed that intracisternal administration of TGF-beta3 caused increases in the NA levels in the PVH and VMH. Then, we investigated the impact of impairment of noradrenergic neurons in the PVH and VMH by neurotoxin 6-hydroxydopamine microinjection (NA-lesion) on the action of intracisternal administration of TGF-beta. The NA lesion completely abolished the regulatory effect of TGF-beta on fat oxidation. These results suggest that TGF-beta in the brain enhances fat oxidation via noradrenergic neurons in the PVH and VMH.
- Published
- 2007
27. Enhanced insulin sensitivity in skeletal muscle and liver by physiological overexpression of SIRT6
- Author
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Stefania Pucciarelli, Giorgio Ramadori, Rafael M. Ioris, Benedetta Moreschini, Cristina Andreani, Teppei Fujikawa, Roberto Coppari, Eric D. Berglund, Jason G. Anderson, Katie C. Coate, Mirco Galiè, and Augusto Amici
- Subjects
endogenous glucose appearance rate ,intraperitoneal glucose tolerance test ,EndoRa, endogenous glucose appearance rate ,intraperitoneal pyruvate tolerance test ,endocrine system diseases ,type 2 diabetes mellitus ,Bioinformatics ,high-caloric diet ,Glucose homeostasis ,GIR, glucose infusion rate ,HCD, high-caloric diet ,2. Zero hunger ,glucose disposal rate ,tissue-specific glucose uptake rate ,biology ,GIR ,HCD ,Confounding ,Diabetes ,BAC, bacterial artificial chromosome ,IPGTT, intraperitoneal glucose tolerance test ,IPPTT, intraperitoneal pyruvate tolerance test ,Insulin sensitivity ,Rd, glucose disposal rate ,Rg, tissue-specific glucose uptake rate ,SIRT6 overexpression ,Sirtuin ,T2DM, type 2 diabetes mellitus ,3. Good health ,medicine.anatomical_structure ,Original Article ,SIRT6 ,lcsh:Internal medicine ,medicine.medical_specialty ,T2DM ,glucose infusion rate ,IPGTT ,Internal medicine ,Diabetes mellitus ,medicine ,Rg ,ddc:612 ,lcsh:RC31-1245 ,Molecular Biology ,Rd ,BAC ,business.industry ,nutritional and metabolic diseases ,Skeletal muscle ,Type 2 Diabetes Mellitus ,Cell Biology ,medicine.disease ,Obesity ,Endocrinology ,biology.protein ,IPPTT ,bacterial artificial chromosome ,business ,EndoRa - Abstract
Objective Available treatment for obesity and type 2 diabetes mellitus (T2DM) is suboptimal. Thus, identifying novel molecular target(s) exerting protective effects against these metabolic imbalances is of enormous medical significance. Sirt6 loss- and gain-of-function studies have generated confounding data regarding the role of this sirtuin on energy and glucose homeostasis, leaving unclear whether activation or inhibition of SIRT6 may be beneficial for the treatment of obesity and/or T2DM. Methods To address these issues, we developed and studied a novel mouse model designed to produce eutopic and physiological overexpression of SIRT6 (Sirt6BAC mice). These mutants and their controls underwent several metabolic analyses. These include whole-blood reverse phase high-performance liquid chromatography assay, glucose and pyruvate tolerance tests, hyperinsulinemic-euglycemic clamp assays, and assessment of basal and insulin-induced level of phosphorylated AKT (p-AKT)/AKT in gastrocnemius muscle. Results Sirt6BAC mice physiologically overexpress functionally competent SIRT6 protein. While Sirt6BAC mice have normal body weight and adiposity, they are protected from developing high-caloric-diet (HCD)-induced hyperglycemia and glucose intolerance. Also, Sirt6BAC mice display increased circulating level of the polyamine spermidine. The ability of insulin to suppress endogenous glucose production was significantly enhanced in Sirt6BAC mice compared to wild-type controls. Insulin-stimulated glucose uptake was increased in Sirt6BAC mice in both gastrocnemius and soleus muscle, but not in brain, interscapular brown adipose, or epididymal adipose tissue. Insulin-induced p-AKT/AKT ratio was increased in gastrocnemius muscle of Sirt6BAC mice compared to wild-type controls. Conclusions Our data indicate that moderate, physiological overexpression of SIRT6 enhances insulin sensitivity in skeletal muscle and liver, engendering protective actions against diet-induced T2DM. Hence, the present study provides support for the anti-T2DM effect of SIRT6 and suggests SIRT6 as a putative molecular target for anti-T2DM treatment., Highlights • “Sirt6BAC” mice overexpress SIRT6 in a physiological manner unattained previously. • SIRT6 overexpression protects against aberrant glucose homeostasis. • Sirt6BAC mice exhibit enhanced insulin sensitivity in skeletal muscle and liver. • Pharmacologically enhancing SIRT6 activity may be a viable way to treat diabetes.
- Published
- 2015
28. Elevated resistin levels induce central leptin resistance and increased atherosclerotic progression in mice
- Author
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Caroline Tao, You-Ree Cho, Teppei Fujikawa, Philipp E. Scherer, Rana K. Gupta, Zhao V. Wang, Makoto Fukuda, Joel K. Elmquist, Joseph M. Rutkowski, and Ingrid Wernstedt Asterholm
- Subjects
Leptin ,Male ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,Type 2 diabetes ,Article ,Mice ,Insulin resistance ,Downregulation and upregulation ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,Medicine ,Animals ,Resistin ,Obesity ,Triglycerides ,business.industry ,nutritional and metabolic diseases ,respiratory system ,medicine.disease ,Atherosclerosis ,Mice, Inbred C57BL ,Endocrinology ,Adipose Tissue ,Diabetes Mellitus, Type 2 ,Receptors, LDL ,Immunology ,Macrophages, Peritoneal ,Female ,Insulin Resistance ,business ,hormones, hormone substitutes, and hormone antagonists - Abstract
Resistin was originally identified as an adipocyte-derived factor upregulated during obesity and as a contributor to obesity-associated insulin resistance. Clinically, resistin has also been implicated in cardiovascular disease in a number of different patient populations. Our aim was to simultaneously address these phenomena.We generated mice with modest adipocyte-specific resistin overexpression. These mice were crossed with mice deficient in the LDL receptor (Ldlr (-/-)) to probe the physiological role of resistin. Both metabolic and atherosclerotic assessments were performed.Resistin overexpression led to increased atherosclerotic progression in Ldlr (-/-) mice. This was in part related to elevated serum triacylglycerol levels and a reduced ability to clear triacylglycerol upon a challenge. Additional phenotypic changes, such as increased body weight and reduced glucose clearance, independent of the Ldlr (-/-) background, confirmed increased adiposity associated with a more pronounced insulin resistance. A hallmark of elevated resistin was the disproportionate increase in circulating leptin levels. These mice thus recapitulated both the proposed negative cardiovascular correlation and the insulin resistance. A unifying mechanism for this complex phenotype was a resistin-mediated central leptin resistance, which we demonstrate directly both in vivo and in organotypic brain slices. In line with reduced sympathetic nervous system outflow, we found decreased brown adipose tissue (BAT) activity. The resulting elevated triacylglycerol levels provide a likely explanation for accelerated atherosclerosis.Resistin overexpression leads to a complex metabolic phenotype driven by resistin-mediated central leptin resistance and reduced BAT activity. Hypothalamic leptin resistance thus provides a unifying mechanism for both resistin-mediated insulin resistance and enhanced atherosclerosis.
- Published
- 2014
29. Revisiting the Ventral Medial Nucleus of the Hypothalamus: The Roles of SF-1 Neurons in Energy Homeostasis
- Author
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Yun Hee Choi, Anne L. Reuter, Teppei Fujikawa, Jiwon Lee, and Ki Woo Kim
- Subjects
Steroidogenic factor 1 ,obesity ,General Neuroscience ,Ventral medial nucleus ,knockout ,Review Article ,Biology ,Steroidogenic Factor 1 ,Energy homeostasis ,lcsh:RC321-571 ,ventral medial hypothalamic nucleus ,medicine.anatomical_structure ,Hypothalamus ,Genetic model ,medicine ,Glucose homeostasis ,glucose homeostasis ,arcuate nucleus of the hypothalamus ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Nucleus ,Neuroscience ,energy homeostasis ,Homeostasis ,steroidogenic factor-1 - Abstract
Obesity, diabetes, and other metabolic complications are growing concerns for public health and could lead to detrimental life-threatening conditions. Neurons whose activities are required for energy and glucose homeostasis are found in a number of hypothalamic nuclei. In the early twentieth century, the ventral medial nucleus of the hypothalamus (VMH) was the first site reported to play a prominent role in the regulation of energy homeostasis through control of food intake and energy expenditure. Recent studies using sophisticated genetic tools have further highlighted the importance of the VMH and have extended our understanding of the physiological role of the nucleus in regulation of energy homeostasis. These genetic studies were preceded by the identification of steroidogenic factor-1 (SF-1) as a marker of the VMH. This review focuses on the emerging homeostatic roles of the SF-1 neurons in the VMH discovered through the use of genetic models, particularly highlighting the control of energy, and glucose homeostasis.
- Published
- 2013
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30. Leptin engages a hypothalamic neurocircuitry to permit survival in the absence of insulin
- Author
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Teppei Fujikawa, Claudia R. Vianna, Linh Vong, Pedro Luis Herrera, Pierre Baldi, Joel K. Elmquist, Simona Chera, Vishal R. Patel, Bradford B. Lowell, Roberto Coppari, Eric D. Berglund, Giorgio Ramadori, and Fabrizio Thorel
- Subjects
Leptin ,Physiology ,Glucose uptake ,medicine.medical_treatment ,Adipose tissue ,Kaplan-Meier Estimate ,Medical Biochemistry and Metabolomics ,Mice ,0302 clinical medicine ,Receptors ,Brown adipose tissue ,Insulin ,2.1 Biological and endogenous factors ,ddc:576.5 ,GABAergic Neurons ,Aetiology ,Receptor ,Neurons ,0303 health sciences ,Diabetes ,digestive, oral, and skin physiology ,Skeletal ,medicine.anatomical_structure ,Liver ,Adipose Tissue ,Muscle ,hormones, hormone substitutes, and hormone antagonists ,medicine.medical_specialty ,Hypothalamus ,Biology ,Experimental ,Endocrinology & Metabolism ,03 medical and health sciences ,Diabetes mellitus ,Internal medicine ,Diabetes Mellitus ,medicine ,Animals ,Obesity ,ddc:612 ,Molecular Biology ,Metabolic and endocrine ,Nutrition ,030304 developmental biology ,Leptin receptor ,Neurosciences ,Brown ,Cell Biology ,medicine.disease ,Glucose ,Endocrinology ,Hyperglycemia ,Biochemistry and Cell Biology ,030217 neurology & neurosurgery - Abstract
SummaryThe dogma that life without insulin is incompatible has recently been challenged by results showing the viability of insulin-deficient rodents undergoing leptin monotherapy. Yet, the mechanisms underlying these actions of leptin are unknown. Here, the metabolic outcomes of intracerebroventricular (i.c.v.) administration of leptin in mice devoid of insulin and lacking or re-expressing leptin receptors (LEPRs) only in selected neuronal groups were assessed. Our results demonstrate that concomitant re-expression of LEPRs only in hypothalamic γ-aminobutyric acid (GABA) and pro-opiomelanocortin (POMC) neurons is sufficient to fully mediate the lifesaving and antidiabetic actions of leptin in insulin deficiency. Our analyses indicate that enhanced glucose uptake by brown adipose tissue and soleus muscle, as well as improved hepatic metabolism, underlies these effects of leptin. Collectively, our data elucidate a hypothalamic-dependent pathway enabling life without insulin and hence pave the way for developing better treatments for diseases of insulin deficiency.
- Published
- 2013
31. Blood lactate functions as a signal for enhancing fatty acid metabolism during exercise via TGF-β in the brain
- Author
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Hiroyuki, Yamada, Yoko, Iwaki, Ryo, Kitaoka, Mina, Fujitani, Tetsuro, Shibakusa, Teppei, Fujikawa, Shigenobu, Matsumura, Tohru, Fushiki, and Kazuo, Inoue
- Subjects
Male ,Rats, Sprague-Dawley ,Transforming Growth Factor beta ,Fatty Acids ,Physical Exertion ,Animals ,Brain ,Lactic Acid ,Energy Metabolism ,Rats ,Signal Transduction - Abstract
Moderate-intensity running (treadmill velocity of 21 m/min) increased blood lactate and actived transforming growth factor-β (TGF-β) concentration in rat cerebrospinal fluid (CSF). On the other hand, low-intensity running (15 m/min) did not increase blood lactate and caused no change in CSF TGF-β. Intraperitoneal (i.p.) administration of lactate to anesthetized rats caused an increase in blood lactate similar to that observed after a 21 m/min running exercise and increased the level of active TGF-β in CSF. Intraperitoneal administration of lactate at the same dose to awake and unrestricted rats caused a decrease in the respiratory exchange ratio, that is, enhancement of fatty acid oxidation and depression of spontaneous motor activity (SMA). Given that intracisternal administration of TGF-β to rats has been reported to enhance fatty acid metabolism and to depress SMA, we surmise that the observed changes caused by i.p. lactate administration in this study were mediated, at least in part, by TGF-β in the brain.
- Published
- 2012
32. SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance
- Author
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Jason G. Anderson, Giorgio Ramadori, Claudia R. Vianna, Eric D. Berglund, Shaday Michan, David A. Sinclair, Carol F. Elias, Roberto Coppari, Teppei Fujikawa, and Renata Frazão
- Subjects
Steroidogenic factor 1 ,Leptin ,Patch-Clamp Techniques ,endocrine system diseases ,Physiology ,medicine.medical_treatment ,Gene Expression ,Steroidogenic Factor 1 ,Mice ,0302 clinical medicine ,Sirtuin 1 ,Insulin ,Neurons ,0303 health sciences ,biology ,Intracellular Signaling Peptides and Proteins ,Immunohistochemistry ,medicine.anatomical_structure ,Gene Knockdown Techniques ,Female ,medicine.medical_specialty ,Hypothalamus ,Mice, Transgenic ,Motor Activity ,Diet, High-Fat ,Article ,03 medical and health sciences ,Insulin resistance ,Internal medicine ,medicine ,Animals ,Obesity ,Molecular Biology ,030304 developmental biology ,Orexins ,Neuropeptides ,Type 2 Diabetes Mellitus ,Skeletal muscle ,Cell Biology ,medicine.disease ,Dietary Fats ,Endocrinology ,Diabetes Mellitus, Type 2 ,biology.protein ,Insulin Resistance ,Energy Metabolism ,030217 neurology & neurosurgery - Abstract
SummaryChronic feeding on high-calorie diets causes obesity and type 2 diabetes mellitus (T2DM), illnesses that affect hundreds of millions. Thus, understanding the pathways protecting against diet-induced metabolic imbalance is of paramount medical importance. Here, we show that mice lacking SIRT1 in steroidogenic factor 1 (SF1) neurons are hypersensitive to dietary obesity owing to maladaptive energy expenditure. Also, mutant mice have increased susceptibility to developing dietary T2DM due to insulin resistance in skeletal muscle. Mechanistically, these aberrations arise, in part, from impaired metabolic actions of the neuropeptide orexin-A and the hormone leptin. Conversely, mice overexpressing SIRT1 in SF1 neurons are more resistant to diet-induced obesity and insulin resistance due to increased energy expenditure and enhanced skeletal muscle insulin sensitivity. Our results unveil important protective roles of SIRT1 in SF1 neurons against dietary metabolic imbalance.
- Published
- 2011
33. Noradrenergic projections to the ventromedial hypothalamus regulate fat metabolism during endurance exercise
- Author
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Ryo Kitaoka, Kazuo Inoue, N. Hirano, Shigenobu Matsumura, Teppei Fujikawa, Tohru Fushiki, and Takashi Miyaki
- Subjects
Male ,medicine.medical_specialty ,Microdialysis ,Rats, Sprague-Dawley ,Norepinephrine ,Dopamine ,Endurance training ,Internal medicine ,Physical Conditioning, Animal ,Monoaminergic ,Neural Pathways ,medicine ,Animals ,Oxidopamine ,Beta oxidation ,Neurons ,Medulla Oblongata ,Chemistry ,General Neuroscience ,Lipid Metabolism ,Rats ,Endocrinology ,Hypothalamus ,Ventromedial Hypothalamic Nucleus ,Medulla oblongata ,Physical Endurance ,Serotonin ,Energy Metabolism ,medicine.drug - Abstract
The regulation of energy metabolism by the central nervous system during endurance exercise was examined. We conducted respiratory gas analysis by functionally paralyzing the ventromedial hypothalamus (VMH), the lateral hypothalamic area, and the paraventricular nucleus of the hypothalamus with local anaesthetic (lidocaine) during treadmill running at a velocity that allowed for efficient fatty acid oxidation. Our results showed that only the lidocaine treatment of the VMH attenuated fatty acid oxidation during endurance exercise. The monoaminergic neural activities at these nuclei during in vivo microdialysis in rats under the same conditions indicated a significant increase in the extracellular concentration of noradrenaline in all nuclei. Similarly, a significant increase in dopamine occurred at some points during exercise, but no change in serotonin concentration occurred regardless of exercise. Disruption of noradrenergic projections to the VMH by 6-hydroxydopamine attenuated the enhancement of fat oxidation during running. Blocker treatments clarified that noradrenergic inputs to the VMH are mediated by β-adrenoceptors. These data indicate that information about peripheral tissues status is transmitted via noradrenergic projections originating in the medulla oblongata, which may be an important contribution by the VMH and its downstream mechanisms to enhanced fatty acid oxidation during exercise.
- Published
- 2010
34. Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice
- Author
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Ichiro Sakata, Giorgio Ramadori, Teppei Fujikawa, Jen Chieh Chuang, and Roberto Coppari
- Subjects
Central Nervous System ,Leptin ,Male ,medicine.medical_specialty ,Preproinsulin ,medicine.medical_treatment ,Diabetes Mellitus, Experimental ,Placebos ,chemistry.chemical_compound ,Mice ,Proopiomelanocortin ,Internal medicine ,Insulin-Secreting Cells ,medicine ,Animals ,Humans ,Insulin ,Protein Precursors ,Muscle, Skeletal ,Pancreas ,Injections, Intraventricular ,Type 1 diabetes ,Multidisciplinary ,Leptin receptor ,biology ,Glycogen ,digestive, oral, and skin physiology ,Biological Sciences ,Neuropeptide Y receptor ,medicine.disease ,Disease Models, Animal ,Endocrinology ,Diabetes Mellitus, Type 1 ,chemistry ,biology.protein ,Receptors, Leptin ,hormones, hormone substitutes, and hormone antagonists - Abstract
Leptin monotherapy reverses the deadly consequences and improves several of the metabolic imbalances caused by insulin-deficient type 1 diabetes (T1D) in rodents. However, the mechanism(s) underlying these effects is totally unknown. Here, we report that intracerebroventricular (icv) infusion of leptin reverses lethality and greatly improves hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency in mice. Notably, icv leptin administration leads to increased body weight while suppressing food intake, thus correcting the catabolic consequences of T1D. Also, icv leptin delivery improves expression of the metabolically relevant hypothalamic neuropeptides proopiomelanocortin, neuropeptide Y, and agouti-related peptide in T1D mice. Furthermore, this treatment normalizes phosphoenolpyruvate carboxykinase 1 contents without affecting glycogen levels in the liver. Pancreatic β-cell regeneration does not underlie these beneficial effects of leptin, because circulating insulin levels were undetectable at basal levels and following a glucose overload. Also, pancreatic preproinsulin mRNA was completely absent in these icv leptin-treated T1D mice. Furthermore, the antidiabetic effects of icv leptin administration rapidly vanished (i.e., within 48 h) after leptin treatment was interrupted. Collectively, these results unveil a key role for the brain in mediating the antidiabetic actions of leptin in the context of T1D.
- Published
- 2010
35. Intracisternal administration of transforming growth factor-beta evokes fever through the induction of cyclooxygenase-2 in brain endothelial cells
- Author
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Shigenobu Matsumura, Teppei Fujikawa, Hiroyuki Yamada, Tohru Fushiki, Kiyoshi Matsumura, Tetsuro Shibakusa, and Kazuo Inoue
- Subjects
Male ,medicine.medical_specialty ,Fever ,Physiology ,Cellular differentiation ,medicine.medical_treatment ,Activin Receptors ,Biology ,Dinoprostone ,Proinflammatory cytokine ,Body Temperature ,Rats, Sprague-Dawley ,Transforming Growth Factor beta ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Endothelium ,Tissue homeostasis ,Dose-Response Relationship, Drug ,Cell growth ,Brain ,Cell biology ,Rats ,Endothelial stem cell ,Endocrinology ,Cytokine ,Eicosanoid ,Cyclooxygenase 2 ,Enzyme Induction ,Receptors, Transforming Growth Factor beta ,Transforming growth factor - Abstract
Transforming growth factor-β (TGF-β), a pleiotropic cytokine, regulates cell proliferation, differentiation, and apoptosis, and plays a key role in development and tissue homeostasis. TGF-β functions as an anti-inflammatory cytokine because it suppresses microglia and B-lymphocyte functions, as well as the production of proinflammatory cytokines. However, we previously demonstrated that the intracisternal administration of TGF-β induces fever like that produced by proinflammatory cytokines. In this study, we investigated the mechanism of TGF-β-induced fever. The intracisternal administration of TGF-β increased body temperature in a dose-dependent manner. Pretreatment with cyclooxygenase-2 (COX-2)-selective inhibitor significantly suppressed TGF-β-induced fever. COX-2 is known as one of the rate-limiting enzymes of the PGE2synthesis pathway, suggesting that fever induced by TGF-β is COX-2 and PGE2dependent. TGF-β increased PGE2levels in cerebrospinal fluid and increased the expression of COX-2 in the brain. Double immunostaining of COX-2 and von Willebrand factor (vWF, an endothelial cell marker) revealed that COX-2-expressing cells were mainly endothelial cells. Although not all COX-2-immunoreactive cells express TGF-β receptor, some COX-2-immunoreactive cells express activin receptor-like kinase-1 (ALK-1, an endothelial cell-specific TGF-β receptor), suggesting that TGF-β directly or indirectly acts on endothelial cells to induce COX-2 expression. These findings suggest a novel function of TGF-β as a proinflammatory cytokine in the central nervous system.
- Published
- 2007
36. Living without insulin: the role of leptin signaling in the hypothalamus
- Author
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Teppei Fujikawa and Roberto Coppari
- Subjects
diabetes mellitus type 1 ,medicine.medical_specialty ,insulin ,diabetes mellitus type 2 ,medicine.medical_treatment ,Central nervous system ,Review ,Carbohydrate metabolism ,leptin ,lcsh:RC321-571 ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Medicine ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,030304 developmental biology ,0303 health sciences ,Leptin receptor ,business.industry ,General Neuroscience ,Insulin ,Leptin ,medicine.disease ,central nervous system ,Diabetes Mellitus, Type 1 ,medicine.anatomical_structure ,Diabetes Mellitus, Type 2 ,Hypothalamus ,diabetes mellitus ,leptin receptors ,Leptin signaling ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Since its discovery in 1922, insulin has been thought to be required for normal metabolic homeostasis and survival. However, this view would need to be revised as recent results from different laboratories have convincingly indicated that life without insulin is possible in rodent models. These data indicate that particular neuronal circuitries, which include hypothalamic leptin-responsive neurons, are empowered with the capability of permitting life in complete absence of insulin. Here, we review the neuronal and peripheral mechanisms by which leptin signaling in the central nervous system (CNS) regulates glucose metabolism in an insulin-independent manner.
- Published
- 2015
37. Mechanism of activation of transforming growth factor-beta in the brain by exercise
- Author
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Hiroyuki Yamada, Kazuo Inoue, Teppei Fujikawa, Tohru Fushiki, Yoko Iwaki, and Shigenobu Matsumura
- Subjects
biology ,Chemistry ,Mechanism (biology) ,General Neuroscience ,biology.protein ,General Medicine ,Transforming growth factor beta ,Transforming growth factor ,Cell biology - Published
- 2007
38. Xbp1s in Pomc Neurons Connects ER Stress with Energy Balance and Glucose Homeostasis
- Author
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Eric D. Berglund, Tianya Liu, Joel K. Elmquist, Lin Jia, Philipp E. Scherer, Yingfeng Deng, Yongsheng Chang, Tiemin Liu, Makoto Fukuda, Syann Lee, Jong Woo Sohn, Kevin W. Williams, Kai Sun, Zhuo Deng, Charlotte E. Lee, Daisuke Kohno, Xingxing Kong, Teppei Fujikawa, Michael Scott, and Yong Gao
- Subjects
Leptin ,Male ,X-Box Binding Protein 1 ,medicine.medical_specialty ,endocrine system ,Pro-Opiomelanocortin ,Physiology ,medicine.medical_treatment ,Regulatory Factor X Transcription Factors ,Carbohydrate metabolism ,Biology ,Diet, High-Fat ,Mice ,Insulin resistance ,Downregulation and upregulation ,Internal medicine ,medicine ,Glucose homeostasis ,Animals ,Homeostasis ,Insulin ,Obesity ,Molecular Biology ,Neurons ,digestive, oral, and skin physiology ,Cell Biology ,medicine.disease ,Endoplasmic Reticulum Stress ,Up-Regulation ,DNA-Binding Proteins ,Endocrinology ,Glucose ,Liver ,nervous system ,Unfolded protein response ,Unfolded Protein Response ,Energy Metabolism ,hormones, hormone substitutes, and hormone antagonists ,Transcription Factors - Abstract
SummaryThe molecular mechanisms underlying neuronal leptin and insulin resistance in obesity and diabetes remain unclear. Here we show that induction of the unfolded protein response transcription factor spliced X-box binding protein 1 (Xbp1s) in pro-opiomelanocortin (Pomc) neurons alone is sufficient to protect against diet-induced obesity as well as improve leptin and insulin sensitivity, even in the presence of strong activators of ER stress. We also demonstrate that constitutive expression of Xbp1s in Pomc neurons contributes to improved hepatic insulin sensitivity and suppression of endogenous glucose production. Notably, elevated Xbp1s levels in Pomc neurons also resulted in activation of the Xbp1s axis in the liver via a cell-nonautonomous mechanism. Together our results identify critical molecular mechanisms linking ER stress in arcuate Pomc neurons to acute leptin and insulin resistance as well as liver metabolism in diet-induced obesity and diabetes.
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