Estrogens promote binge alcohol drinking and contribute to sex differences in alcohol use disorder. However, the mechanisms are largely unknown. This study aims to test if estrogens act on ...5-hydroxytryptamine neurons in the dorsal raphe nucleus (5-HT
) to promote binge drinking. We found that female mice drank more alcohol than male mice in chronic drinking in the dark (DID) tests. This sex difference was associated with distinct alterations in mRNA expression of estrogen receptor α (ERα) and 5-HT-related genes in the DRN, suggesting a potential role of estrogen/ERs/5-HT signaling. In supporting this view, 5-HT
neurons from naïve male mice had lower baseline firing activity but higher sensitivity to alcohol-induced excitation compared to 5-HT
neurons from naïve female mice. Notably, this higher sensitivity was blunted by 17β-estradiol treatment in males, indicating an estrogen-dependent mechanism. We further showed that both ERα and ERβ are expressed in 5-HT
neurons, whereas ERα agonist depolarizes and ERβ agonist hyperpolarizes 5-HT
neurons. Notably, both treatments blocked the stimulatory effects of alcohol on 5-HT
neurons in males, even though they have antagonistic effects on the activity dynamics. These results suggest that ERs' inhibitory effects on ethanol-induced burst firing of 5-HT
neurons may contribute to higher levels of binge drinking in females. Consistently, chemogenetic activation of ERα- or ERβ-expressing neurons in the DRN reduced binge alcohol drinking. These results support a model in which estrogens act on ERα/β to prevent alcohol-induced activation of 5-HT
neurons, which in return leads to higher binge alcohol drinking.
Aim
Heparin, a widely used antithrombotic drug has many other anticoagulant‐independent physiological functions. Here, we elucidate a novel role of heparin in glucose homeostasis, suggesting an ...approach for developing heparin‐targeted therapies for diabetes.
Methods
For serum heparin levels and correlation analysis, 122 volunteer’s plasma, DIO (4 weeks HFD) and db/db mice serums were collected and used for spectrophotometric determination. OGTT, ITT, 2‐NBDG uptake and muscle GLUT4 immunofluorescence were detected in chronic intraperitoneal injection of heparin or heparinase (16 days) and muscle‐specific loss‐of‐function mice. In 293T cells, the binding of insulin to its receptor was detected by fluorescence resonance energy transfer (FRET), Myc‐GLUT4‐mCherry plasmid was used in GLUT4 translocation. In vitro, C2C12 cells as mouse myoblast cells were further verified the effects of heparin on glucose homeostasis through 2‐NBDG uptake, Western blot and co‐immunoprecipitation.
Results
Serum concentrations of heparin are positively associated with blood glucose levels in humans and are significantly increased in diet‐induced and db/db obesity mouse models. Consistently, a chronic intraperitoneal injection of heparin results in hyperglycaemia, glucose intolerance and insulin resistance. These effects are independent of heparin’s anticoagulant function and associated with decreases in glucose uptake and translocation of glucose transporter type 4 (GLUT4) in skeletal muscle. By using a muscle‐specific loss‐of‐function mouse model, we further demonstrated that muscle GLUT4 is required for the detrimental effects of heparin on glucose homeostasis.
Conclusions
Heparin reduced insulin binding to its receptor by interacting with insulin and inhibited insulin‐mediated activation of the PI3K/Akt signalling pathway in skeletal muscle, which leads to impaired glucose uptake and hyperglycaemia.
Circulating heparin is positively correlated with blood glucose level in humans and increases in diet‐induced obese and type 2 diabetic db/db mice. Chronic intraperitoneal injection of heparin results in hyperglycemia, glucose intolerance, and insulin resistance. Heparin interacts with insulin to inhibit insulin and insulin receptor binding in skeletal muscle, and by doing so, impairs skeletal muscle GLUT4 translocation and glucose uptake.
Beneficial effects of resistance exercise on metabolic health and particularly muscle hypertrophy and fat loss are well established, but the underlying chemical and physiological mechanisms are not ...fully understood. Here, we identified a myometabolite‐mediated metabolic pathway that is essential for the beneficial metabolic effects of resistance exercise in mice. We showed that substantial accumulation of the tricarboxylic acid cycle intermediate α‐ketoglutaric acid (AKG) is a metabolic signature of resistance exercise performance. Interestingly, human plasma AKG level is also negatively correlated with BMI. Pharmacological elevation of circulating AKG induces muscle hypertrophy, brown adipose tissue (BAT) thermogenesis, and white adipose tissue (WAT) lipolysis in vivo. We further found that AKG stimulates the adrenal release of adrenaline through 2‐oxoglutarate receptor 1 (OXGR1) expressed in adrenal glands. Finally, by using both loss‐of‐function and gain‐of‐function mouse models, we showed that OXGR1 is essential for AKG‐mediated exercise‐induced beneficial metabolic effects. These findings reveal an unappreciated mechanism for the salutary effects of resistance exercise, using AKG as a systemically derived molecule for adrenal stimulation of muscle hypertrophy and fat loss.
Synopsis
The mechanisms underlying the beneficial effects of resistance exercise on body metabolism are poorly understood. Here, the Krebs cycle intermediate α‐ketoglutaric acid (AKG) is identified as an exercise‐induced, muscle‐derived metabolite, enhancing muscle growth and lipolysis via systemic stimulation of the adrenal gland.
Acute resistance exercise increases plasma AKG levels and muscular AKG synthesis.
AKG induces muscle hypertrophy and fat loss in vivo in mouse obesity models.
AKG activates the adrenal gland, enhancing enhanced thermogenesis and lipolysis.
OXGR1 is required for AKG‐mediated secretion of serum E.
The Krebs cycle intermediate α‐ketoglutaric acid acts as a systemic myometabolite promoting energy expenditure and lipolysis in mice.
The preoptic anterior hypothalamus (POAH) , known as a thermointegrative center, modulates metabolic adaptation in response to temperature change, thus making it relevant for body weight homeostasis. ...Forkhead transcription factor O1 (FoxO1) plays an important role in mediating effects of leptin and insulin on metabolic homeostasis in the hypothalamus. However, the homeostatic role of FoxO1 in POAH has not been investigated. We found that FoxO1 specific deletion in the POAH neurons (FoxO1POAH-KO) prevented high fat diet-induced obesity (DIO) in female but not male mice. This female-specific protection was associated with increased lean mass, decreased fat mass, and upregulated thermogenesis in adipose tissues. The female FoxO1POAH-KO mice also showed improved insulin sensitivity and increased energy expenditure when exposed at room temperature (22 °C) or cold (6 °C) . Moreover, the FoxO1POAH-KO-induced protection against DIO in females was blunted by ovariectomy (OVX) , while 17β-estradiol supplementation after OVX failed to restore this protection, suggesting an estrogen-independent mechanism. Finally, mice with FoxO1 constitutively activated in the POAH neurons (FoxO1POAH-CA) significantly increased DIO in both sexes, further supporting an essential metabolic role of FoxO1POAH. Together, these findings indicate that FoxO1POAH is a crucial transcription factor that directs and coordinates control of energy balance, thermogenesis, and glucose homeostasis in female mice.
Key words: FoxO1, POAH, sex difference.
Disclosure
P. Luo: None. H. Ye: None. T. Unterman: None. P. Xu: None.
Funding
P. Xu is supported by National Institutes of Health (R00DK1070 and R01DK123098) , Department of Defense (Innovative Grant W81XWH-19-PRMRP-DA) , and The University of Chicago Diabetes Research and Training Center (The Pilot and Feasibility Award DK020595) .
Oxysterols are metabolites of cholesterol produced in peripheral tissues as a means to eliminate cholesterol. 27-hydroxycholesterol (27HC) is the most abundant oxysterols and can cross the ...blood-brain barrier. Interestingly, 27HC has recently been identified as an endogenous selective estrogen receptor modulator (SERM) for both estrogen receptor α and β (ERα/β) . Considering the regulatory effects of brain estrogen/ERα signaling on energy metabolism, we hypothesize that the endogenous SERM 27HC binds with ERα in the arcuate nucleus of hypothalamus (ARH) of brain to modulate energy homeostasis.In supporting this point of view, we found that a single acute intracerebroventricular (ICV) injection of 27HC inhibited food intake in both male and female mice. The reduced food intake was attributed to decreased meal size and increased intermeal intervals. This anorexigenic effect was also associated with the increased c-fos expression in the pro-opiomelanocortin neurons in ARH (POMCARH) . Using brain slice patch-clamp recording, we consistently showed that 27HC dose-dependently actives POMCARH in an ERα-dependent manner, suggesting a mediating role of ERα expressed by POMCARH neurons. Notably, we further revealed that the inhibitory effects of 27HC on food intake were blocked by antagonists for ERα or POMC downstream melanocortin 3/4 receptors. In addition, chemogenetic inhibition of POMCARH neurons also blunted the anorexigenic effects of 27HC in mice. Collectively, these results support a model that 27HC acutely inhibits food intake by acting on ERα to stimulate POMCARH neuronal activity. This 27HC/ERα/POMC signaling pathway may serve as a critical defending mechanism against high-fat diet-induced obesity.
Disclosure
H. Ye: None. B. Feng: None. D. Dixit: None. Y. He: None. P. Xu: None.
The conversion of skeletal muscle fiber from fast twitch to slow‐twitch is important for sustained and tonic contractile events, maintenance of energy homeostasis, and the alleviation of fatigue. ...Skeletal muscle remodeling is effectively induced by endurance or aerobic exercise, which also generates several tricarboxylic acid (TCA) cycle intermediates, including succinate. However, whether succinate regulates muscle fiber‐type transitions remains unclear. Here, we found that dietary succinate supplementation increased endurance exercise ability, myosin heavy chain I expression, aerobic enzyme activity, oxygen consumption, and mitochondrial biogenesis in mouse skeletal muscle. By contrast, succinate decreased lactate dehydrogenase activity, lactate production, and myosin heavy chain IIb expression. Further, by using pharmacological or genetic loss‐of‐function models generated by phospholipase Cβ antagonists, SUNCR1 global knockout, or SUNCR1 gastrocnemius‐specific knockdown, we found that the effects of succinate on skeletal muscle fiber‐type remodeling are mediated by SUNCR1 and its downstream calcium/NFAT signaling pathway. In summary, our results demonstrate succinate induces transition of skeletal muscle fiber via SUNCR1 signaling pathway. These findings suggest the potential beneficial use of succinate‐based compounds in both athletic and sedentary populations.
Synopsis
Aerobic exercise leads to skeletal muscle remodelling. This study reveals that dietary succinate is sufficient to elicit muscle remodelling and increased endurance in sedentary mice.
Dietary succinate increases endurance exercise ability in mice.
Dietary succinate induces skeletal muscle fiber transition from fast‐twitch to slow‐twitch.
SUNCR1 signaling pathway is required for the succinate induced skeletal muscle remodeling.
Aerobic exercise leads to skeletal muscle remodelling. This study reveals that dietary succinate is sufficient to elicit muscle remodelling and increased endurance in sedentary mice.
The influence of gut bacteria on host energy homeostasis is increasingly recognized, but mechanistic links are lacking. The gut microbiota digests and ferments nutrients, which result in short-chain ...fatty acids (SCFAs) . The body senses these nutrients in large part through free fatty acid receptors 2 (FFA2) and 3 (FFA3) . Accumulating evidence indicates that the gut microbiota/SCFAs interact with the central nervous system (CNS) to regulate brain metabolic function. Consistently, we found that a single acute intracerebroventricular (ICV) injection of acetate (ACE) , propionate (PRO) , or butyrate (BUT) dose-dependently inhibited food intake in an FFA2/3-dependent manner. The reduced food intake induced by ACE, PRO, or BUT was attributed to decreased meal size or increased intermeal interval. These regulatory effects on meal patterns were blunted in FFA2 and FFA3 double-receptor knockout mice, suggesting a mediating role of brain FFA2/3. Interestingly, RNAscope analysis showed that FFA3 but not FFA2 highly expressed in the cerebellar granule neurons. Using brain slice patch-clamp, we consistently showed that PRO or FFA3-selective agonists inhibited these granule neurons. Notably, the hyperpolarization effects of PRO on cerebellar granule neurons were blocked by pertussis toxin (PTX) , a G-protein coupled receptor subunit Gi/o blocker, further supporting an FFA3-Gi/o-mediated inhibition on granule neurons. These results suggest a model that SCFAs inhibit food intake through FFA3 expressed by the cerebellar granule neurons.
Key words: SCFA; Brain; FFA3
Disclosure
P. Luo: None. P. Xu: None. H. Ye: None. B.T. Layden: None. Y. He: None. V.C. Torres Irizarry: None.
Compelling evidence has demonstrated that estradiol and estrogen receptor α/β (ERα/β) play key roles in the central regulation of energy balance and glucose homeostasis. Our previous research showed ...that ERα in the medial amygdala (ERαMeA) mediates estrogenic actions to stimulate physical activity, therefore promotes energy expenditure and prevents diet-induced obesity (DIO). Interestingly, another estrogen receptor, ERβ, is also highly expressed in the MeA. To test the metabolic functions of ERβMeA, we generated a mouse model with ERβ selectively deleted in the MeA (ERβKOMeA) during adulthood using AAV virus-mediated Cre-Lox site-specific recombination. We found that, when fed on a high-fat diet but not on a normal chow diet, compared to the control mice, both male and female ERβKOMeA mice showed decreased body weight gain and fat deposition, which were associated with increased energy expenditure. We further showed that half of the ERαMeA neurons co-express ERβ. In these ERα&β co-expressing MeA neurons, ERα agonist propyl pyrazole trio (PPT) induced ERα-dependent depolarization, while ERβ agonist diarypropionitrile (DPN) induced ERβ-dependent hyperpolarization. Finally, we showed that chemogenetic activation of ERαMeA or ERβMeA neurons induces a similar increase in energy expenditure. Collectively, our results support a model that, estrogen acts on ERα/βMeA neurons to provide bidirectional regulation of body weight and resistance to DIO, whereas activating ERαMeA decreases and activating ERβMeA increases body weight.
Disclosure
H. Ye: None. Y. He: None. L. Ibrahimi: None. S. Schaul: None. P. Luo: None. L. Carrillo-Sáenz: None. P. Lai: None. N. Patel: None. M. Kota: None. D. Dixit: None. P. Xu: None.
Funding
National Institutes of Health (5R00DK107008-04)
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