Myostatin expression is increased by food deprivation in a muscle-specific manner and contributes to muscle atrophy during prolonged food deprivation in mice

During food deprivation (FD), skeletal muscle protein is broken down to produce amino acids for hepatic gluconeogenesis to maintain blood glucose levels. However, it is unclear what role, if any, the secreted antigrowth factor myostatin (MSTN) plays in the muscle atrophy induced by FD. We therefore examined expression and function of MSTN in FD in mice. Two days of FD significantly decreased muscle mass and protein content and increased mRNA levels of ubiquitin ligases MuRF-1 and atrogin-1 in fast-twitch tibialis anterior (TA) muscle but not slow-twitch soleus (Sol) muscle, while 2 days of refeeding returned these to fed values in TA. MSTN mRNA levels were significantly increased approximately threefold by 2 days, but not 1 day, of FD and returned to fed levels with 2 days of refeeding in TA but were not significantly affected by FD or refeeding in Sol. TA mass decreased to a similar amount after 1 day of FD in wild-type mice and mice null for the MSTN gene but was decreased to a greater amount in wild-type than MSTN-null mice by 2 days of FD. In addition, blood glucose levels decreased and corticosterone levels increased to a greater extent in MSTN-null mice after 2 days of FD, but surprisingly muscle MuRF-1 and atrogin-1 mRNA levels were not affected by the lack of MSTN during FD. Similarly, changes in hepatic enzyme expression in response to FD were identical between wild-type and MSTN-null mice. Our data are consistent with the hypothesis that MSTN is dispensable for the initial atrophy occurring in response to FD but attenuates the decrease in fast-twitch muscle mass during prolonged FD.

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Nighttime Administration of Nicotine Improves Hepatic Glucose Metabolism via the Hypothalamic Orexin System in Mice

Endocrinology ◽

10.1210/en.2015-1488 ◽

2016 ◽

Vol 157 (1) ◽

pp. 195-206 ◽

Cited By ~ 10

Author(s):

Hiroshi Tsuneki ◽

Takashi Nagata ◽

Mikio Fujita ◽

Kanta Kon ◽

Naizhen Wu ◽

...

Keyword(s):

Blood Glucose ◽

Glucose Metabolism ◽

Oral Intake ◽

Mrna Levels ◽

Active Period ◽

Wild Type ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Deficient Mice

Abstract Nicotine is known to affect the metabolism of glucose; however, the underlying mechanism remains unclear. Therefore, we here investigated whether nicotine promoted the central regulation of glucose metabolism, which is closely linked to the circadian system. The oral intake of nicotine in drinking water, which mainly occurred during the nighttime active period, enhanced daily hypothalamic prepro-orexin gene expression and reduced hyperglycemia in type 2 diabetic db/db mice without affecting body weight, body fat content, and serum levels of insulin. Nicotine administered at the active period appears to be responsible for the effect on blood glucose, because nighttime but not daytime injections of nicotine lowered blood glucose levels in db/db mice. The chronic oral treatment with nicotine suppressed the mRNA levels of glucose-6-phosphatase, the rate-limiting enzyme of gluconeogenesis, in the liver of db/db and wild-type control mice. In the pyruvate tolerance test to evaluate hepatic gluconeogenic activity, the oral nicotine treatment moderately suppressed glucose elevations in normal mice and mice lacking dopamine receptors, whereas this effect was abolished in orexin-deficient mice and hepatic parasympathectomized mice. Under high-fat diet conditions, the oral intake of nicotine lowered blood glucose levels at the daytime resting period in wild-type, but not orexin-deficient, mice. These results indicated that the chronic daily administration of nicotine suppressed hepatic gluconeogenesis via the hypothalamic orexin-parasympathetic nervous system. Thus, the results of the present study may provide an insight into novel chronotherapy for type 2 diabetes that targets the central cholinergic and orexinergic systems.

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Milnacipran, a serotonin and norepinephrine reuptake inhibitor, induces appetite-suppressing effects without inducing hypothalamic stress responses in mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00527.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. R1775-R1781 ◽

Cited By ~ 8

Author(s):

Katsunori Nonogaki ◽

Kana Nozue ◽

Tomifusa Kuboki ◽

Yoshitomo Oka

Keyword(s):

Blood Glucose ◽

Food Intake ◽

Receptor Antagonist ◽

Reuptake Inhibitor ◽

Plasma Corticosterone ◽

Cytokine Signaling ◽

Mrna Levels ◽

Wild Type ◽

Glucose Levels ◽

Blood Glucose Levels

Milnacipran, a selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor, increases extracellular 5-HT and NA levels equally in the central nervous system. Here, we report that systemic administration of milnacipran (20–60 mg/kg) significantly suppressed food intake after fasting in C57BL6J mice. The appetite-suppressing effects of milnacipran were sustained for 5 h. Neither SB242084, a selective 5-HT2C receptor antagonist, nor SB224289, a selective 5-HT1B receptor antagonist, reversed the appetite-suppressing effects of milnacipran. Milnacipran suppressed food intake and body weight in wild-type mice and in Ay mice, which have ectopic expression of the agouti protein. Moreover, milnacipran significantly increased hypothalamic proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA levels, while having no effect on hypothalamic neuropeptide Y, ghrelin, corticotropin-releasing hormone (CRH), and suppressor of cytokine signaling-3 mRNA levels. Interestingly, milnacipran did not increase plasma corticosterone and blood glucose levels, whereas fenfluramine, which inhibits 5-HT reuptake and stimulates 5-HT release, significantly increased plasma corticosterone and blood glucose levels in association with increased hypothalamic CRH mRNA levels. The appetite-suppressing effects of milnacipran had no effects on food intake in food-restricted, wild-type mice and Ay mice. On the other hand, fenfluramine suppressed food intake in food-restricted wild-type mice, but it had no effects in food-restricted Ay mice. These results suggest that inhibition of 5-HT and NA reuptake induces appetite-suppressing effects independent of 5-HT2C and 5-HT1B receptors, and increases hypothalamic POMC and CART gene expression without increasing plasma corticosterone and blood glucose levels in mice.

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Altered Glucose and Insulin Responses to Brain Medullary Thyrotropin-Releasing Hormone (TRH)-Induced Autonomic Activation in Type 2 Diabetic Goto-Kakizaki Rats

Endocrinology ◽

10.1210/en.2005-0553 ◽

2005 ◽

Vol 146 (12) ◽

pp. 5425-5432 ◽

Cited By ~ 7

Author(s):

Yan Ao ◽

Natalie Toy ◽

Moon K. Song ◽

Vay Liang W. Go ◽

Hong Yang

Keyword(s):

Insulin Secretion ◽

Blood Glucose ◽

Wistar Rats ◽

Mrna Levels ◽

Gk Rats ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Autonomic Activation ◽

Insulin Responses

Insulin secretion is impaired in type 2 diabetes (T2D). The insulin and glucose responses to central autonomic activation induced by excitation of brain medullary TRH receptors were studied in T2D Goto-Kakizaki (GK) rats. Blood glucose levels in normally fed, pentobarbital-anesthetized GK and nondiabetic Wistar rats were 193 and 119 mg/100 ml in males and 214 and 131 mg/100 ml in females. Intracisternal injection (ic) of the stable TRH analog RX 77368 (10 ng) induced significantly higher insulin response in both genders of overnight-fasted GK rats compared with Wistar rats and slightly increased blood glucose in female Wistar rats but significantly decreased it from 193 to 145 mg/100 ml in female GK rats. RX 77368 (50 ng) ic induced markedly greater glucose and relatively weaker insulin responses in male GK rats than Wistar rats. Bilateral vagotomy blocked ic RX 77368-induced insulin secretion, whereas adrenalectomy abolished its hyperglycemic effect. In adrenalectomized male GK but not Wistar rats, ic RX 77368 (50 ng) dramatically increased serum insulin levels by 6.5-fold and decreased blood glucose levels from 154 to 98 mg/100 ml; these changes were prevented by vagotomy. GK rats had higher basal pancreatic insulin II mRNA levels but a lower response to ic RX 77368 (50 ng) compared with Wistar rats. These results indicate that central-vagal activation-induced insulin secretion is susceptible in T2D GK rats. However, the dominant sympathetic-adrenal response to medullary TRH plays a suppressing role on vagal-mediated insulin secretion. This unbalanced vago-sympathetic activation by medullary TRH may contribute to the impaired insulin secretion in T2D.

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Feedback regulation of hepatic gluconeogenesis through modulation of SHP/Nr0b2 gene expression by Sirt1 and FoxO1

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00524.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. E312-E320 ◽

Cited By ~ 41

Author(s):

Dan Wei ◽

Rongya Tao ◽

Yao Zhang ◽

Morris F. White ◽

X. Charlie Dong

Keyword(s):

Gene Expression ◽

Blood Glucose ◽

Catalytic Domain ◽

Wild Type Mouse ◽

Diabetic Mouse ◽

Luciferase Reporter ◽

Wild Type ◽

Hepatic Gluconeogenesis ◽

Glucose Levels ◽

Blood Glucose Levels

Protein deacetylase Sirt1 has been implicated in the regulation of hepatic gluconeogenesis; however, the mechanisms are not fully understood. To further elucidate how Sirt1 regulates gluconeogenesis, we took a loss-of-function approach by deleting the coding DNA sequence for the catalytic domain of the Sirt1 gene in the liver of a wild-type mouse (LKOSirt1) or a genetic diabetic mouse in which hepatic insulin receptor substrates 1 and 2 are deleted (DKOIrs1/2). Whereas LKOSirt1 mice exhibited normal levels of fasting and fed blood glucose, inactivation of Sirt1 in DKOIrs1/2 mice (TKOIrs1/2:Sirt1) reduced blood glucose levels and moderately improved systemic glucose tolerance. Pyruvate tolerance was also significantly improved in TKOIrs1/2:Sirt1 mice, suggesting that Sirt1 promotes hepatic gluconeogenesis in this diabetic mouse model. To understand why inactivation of hepatic Sirt1 does not alter blood glucose levels in the wild-type background, we searched for a potential cause and found that expression of small heterodimer partner (SHP, encoded by the Nr0b2 gene), an orphan nuclear receptor, which has been shown to suppress the activity of forkhead transcription factor FoxO1, was decreased in the liver of LKOSirt1 mice. Furthermore, our luciferase reporter assays and chromatin immunoprecipitation analysis revealed that the Nr0b2 gene is a target of FoxO1, which is also regulated by Sirt1. After the gene is upregulated, Nr0b2 can feed back and repress FoxO1- and Sirt1-activated G6pc and Pdk4 gene expression. Thus, our results suggest that Sirt1 can both positively and negatively regulate hepatic gluconeogenesis through FoxO1 and Nr0b2 and keep this physiological process in control.

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Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency

Journal of Endocrinology ◽

10.1677/joe.0.1760237 ◽

2003 ◽

Vol 176 (2) ◽

pp. 237-246 ◽

Cited By ~ 108

Author(s):

K Takeda ◽

K Toda ◽

T Saibara ◽

M Nakagawa ◽

K Saika ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Glucose ◽

Serum Triglyceride ◽

Male Mice ◽

Wild Type ◽

Glucose Levels ◽

Cholesterol Levels ◽

Blood Glucose Levels ◽

Body Weights

Aromatase (CYP19) is a cytochrome P450 enzyme that catalyzes the formation of aromatic C18 estrogens from C19 androgens. It is expressed in various tissues and contributes to sex-specific differences in cellular metabolism. We have generated aromatase-knockout (ArKO) mice in order to study the role of estrogen in the regulation of glucose metabolism. The mean body weights of male ArKO (-/-) mice (n=7) and wild-type littermates (+/+) (n=7) at 10 and 12 weeks of age were 26.7+/-1.9 g vs 26.1+/-0.8 g and 28.8+/-1.4 g vs 26.9+/-1.0 g respectively. The body weights of the ArKO and wild-type mice diverged between 10 and 12 weeks of age with the ArKO males weighing significantly more than their wild-type littermates (P<0.05). The ArKO males showed significantly higher blood glucose levels during an intraperitoneal glucose tolerance test compared with wild-type littermates beginning at 18 weeks of age. By 24 weeks of age, they had higher fasting blood glucose levels compared with wild-type littermates (133.8+/-22.8 mg/dl vs 87.8+/-20.3 mg/dl respectively; P<0.01). An intraperitoneal injection of insulin (0.75 mU insulin/g) caused a continuous decline in blood glucose levels in wild-type mice whereas ArKO males at 18 weeks and older exhibited a rebound increase in glucose levels 30 min after insulin injection. Thus, ArKO male mice appear to develop glucose intolerance and insulin resistance in an age-dependent manner. There was no difference in fasting serum triglyceride and total cholesterol levels between ArKO male mice and wild-type littermates at 13 and 25 weeks of age. However, serum triglyceride and cholesterol levels were significantly elevated following a meal in ArKO mice at 36 weeks of age. Serum testosterone levels in ArKO male mice were continuously higher compared with wild-type littermates. Treatment of ArKO males with 17beta-estradiol improved the glucose response as measured by intraperitoneal glucose and insulin tolerance tests. Treatment with fibrates and thiazolidinediones also led to an improvement in insulin resistance and reduced androgen levels. As complete aromatase deficiency in man is associated with insulin resistance, obesity and hyperlipidemia, the ArKO mouse may be a useful animal model for examining the role of estrogens in the control of glucose and lipid homeostasis.

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The effects of food deprivation and incentive motivation on blood glucose levels and cognitive function

Psychopharmacology ◽

10.1007/s002130050429 ◽

1997 ◽

Vol 134 (1) ◽

pp. 88-94 ◽

Cited By ~ 17

Author(s):

M. W. Green ◽

Nicola A. Elliman ◽

Peter J. Rogers

Keyword(s):

Blood Glucose ◽

Cognitive Function ◽

Food Deprivation ◽

Incentive Motivation ◽

Glucose Levels ◽

Blood Glucose Levels

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An Osteocalcin-deficient mouse strain without endocrine abnormalities

10.1101/732800 ◽

2019 ◽

Author(s):

Cassandra R. Diegel ◽

Steven Hann ◽

Ugur M. Ayturk ◽

Jennifer C.W. Hu ◽

Kyung-eun Lim ◽

...

Keyword(s):

Blood Glucose ◽

Knockout Mice ◽

Male Fertility ◽

Fibroblast Growth Factor 23 ◽

Bone Cell ◽

Wild Type ◽

Double Knockout ◽

Glucose Levels ◽

Blood Glucose Levels

AbstractOsteocalcin (OCN), the most abundant non-collagenous protein in the bone matrix, is reported to be a bone-derived endocrine hormone with wide-ranging effects on many aspects of physiology, including glucose metabolism and male fertility. Many of these observations were made using an OCN-deficient mouse allele (Osc-) in which the 2 OCN-encoding genes in mice, Bglap and Bglap2, were deleted in ES cells by homologous recombination. Here we describe mice with a new Bglap and Bglap2 double knockout (dko) allele (Bglap/2p.Pro25fs17Ter) that was generated by CRISPR/Cas9-mediated gene editing. Mice homozygous for this new allele do not express full length Bglap or Bglap2 mRNA and have no immunodetectable OCN in their plasma. FTIR imaging of cortical and trabecular bone in these homozygous knockout animals finds alterations in the crystal size and maturity of the bone mineral, hydroxyapatite, compared to wild-type littermates; however, μCT and 3-point bending tests do not find differences from wild-type littermates with respect to bone mass and strength. In contrast to the previously reported OCN-deficient mice with the Osc- allele, blood glucose levels and male fertility in the OCN-deficient mice with Bglap/2pPro25fs17Ter allele did not have significant differences from wild-type littermates. We cannot explain the absence of endocrine effects in mice with this new knockout allele. Potential explanations include effects of each mutated allele on the transcription of neighboring genes, and differences in genetic background and environment. So that our findings can be confirmed and extended by other interested investigators, we are donating this new Bglap and Bglap2 double knockout strain to The Jackson Laboratory for academic distribution.Author SummaryCells that make and maintain bone express proteins that function locally or systemically. The former proteins, such as type 1 collagen, affect the material properties of the skeleton while the latter proteins, such as fibroblast growth factor 23, enable the skeleton to communicate with other organ systems. Mutations that affect the functions of most bone cell expressed proteins cause diseases that have similar features in humans and other mammals, such as mice; for example, brittle bone diseases for type 1 collagen mutations and hypophosphatemic rickets for fibroblast growth factor 23 mutations.Our study focuses on another bone cell expressed protein, osteocalcin, which has been suggested to function locally to affect bone strength and systemically as hormone. Studies using osteocalcin knockout mice led other investigators to suggest endocrine roles for osteocalcin in regulating blood glucose levels, male fertility, muscle mass, brain development, behavior and cognition. We therefore decided to generate a new strain of osteocalcin knockout mice that could also be used to investigate these non-skeletal effects.To our surprise the osteocalcin knockout mice we created do not significantly differ from wild-type mice for the 3 phenotypes we examined: bone strength, blood glucose levels, and male fertility. Our data are consistent with findings from osteocalcin knockout rats, but inconsistent with data from the original osteocalcin knockout mice. Because we do not know why our new strain of osteocalcin knockout mice fails to recapitulate phenotypes previously reported for another knockout mouse stain, we have donated our mice to a public repository so that they can be easily obtained and studied in other academic laboratories.

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