RESUMEN
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.
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Ácidos Cetoglutáricos/sangre , Atrofia Muscular/genética , Receptores Purinérgicos P2/genética , Entrenamiento de Fuerza/métodos , Adulto , Anciano , Animales , Línea Celular , Femenino , Técnicas de Inactivación de Genes , Humanos , Masculino , Ratones , Persona de Mediana Edad , Modelos Animales , Atrofia Muscular/metabolismo , Receptores Purinérgicos P2/metabolismoRESUMEN
Obesity is primarily a consequence of consuming calories beyond energetic requirements, but underpinning drivers have not been fully defined. 5-Hydroxytryptamine (5-HT) neurons in the dorsal Raphe nucleus (5-HTDRN) regulate different types of feeding behavior, such as eating to cope with hunger or for pleasure. Here, we observed that activation of 5-HTDRN to hypothalamic arcuate nucleus (5-HTDRN â ARH) projections inhibits food intake driven by hunger via actions at ARH 5-HT2C and 5-HT1B receptors, whereas activation of 5-HTDRN to ventral tegmental area (5-HTDRN â VTA) projections inhibits non-hunger-driven feeding via actions at 5-HT2C receptors. Further, hunger-driven feeding gradually activates ARH-projecting 5-HTDRN neurons via inhibiting their responsiveness to inhibitory GABAergic inputs; non-hunger-driven feeding activates VTA-projecting 5-HTDRN neurons through reducing a potassium outward current. Thus, our results support a model whereby parallel circuits modulate feeding behavior either in response to hunger or to hunger-independent cues.
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Hambre , Serotonina , Núcleo Dorsal del Rafe , Neuronas/fisiología , Área Tegmental Ventral/fisiologíaRESUMEN
Elevations in estrogen (17ß-estradiol, E2) are associated with increased alcohol drinking by women and experimentally in rodents. E2 alters the activity of the dopamine system, including the VTA and its projection targets, which plays an important role in binge drinking. A previous study demonstrated that, during high E2 states, VTA neurons in female mice are more sensitive to ethanol excitation. However, the mechanisms responsible for the ability of E2 to enhance ethanol sensitivity of VTA neurons have not been investigated. In this study, we used selective agonists and antagonists to examine the role of ER subtypes (ERα and ERß) in regulating the ethanol sensitivity of VTA neurons in female mice and found that ERα promotes the enhanced ethanol response of VTA neurons. We also demonstrated that enhancement of ethanol excitation requires the activity of the metabotropic glutamate receptor, mGluR1, which is known to couple with ERα at the plasma membrane. To investigate the behavioral relevance of these findings, we administered lentivirus-expressing short hairpin RNAs targeting either ERα or ERß into the VTA and found that knockdown of each receptor in the VTA reduced binge-like ethanol drinking in female, but not male, mice. Reducing ERα in the VTA had a more dramatic effect on binge-like drinking than reducing ERß, consistent with the ability of ERα to alter ethanol sensitivity of VTA neurons. These results provide important insight into sex-specific mechanisms that drive excessive alcohol drinking.SIGNIFICANCE STATEMENT Estrogen has potent effects on the dopamine system and increases the vulnerability of females to develop addiction to substances, such as alcohol. We investigated the mechanisms by which estrogen increases the response of neurons in the VTA to ethanol. We found that activation of the ERα increased the ethanol-induced excitation of VTA neurons. 17ß-Estradiol-mediated enhancement of ethanol-induced excitation required the metabotropic glutamate receptor mGluR1. We also demonstrated that ERs in the VTA regulate binge-like alcohol drinking by female, but not male, mice. The influence of ERs on binge drinking in female mice suggests that treatments for alcohol use disorder in women may need to account for this sex difference.
Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas/metabolismo , Depresores del Sistema Nervioso Central/farmacología , Receptor alfa de Estrógeno/metabolismo , Etanol/farmacología , Neuronas/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Animales , Consumo Excesivo de Bebidas Alcohólicas/psicología , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Antagonistas de Estrógenos/farmacología , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/agonistas , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ovariectomía , Receptores AMPA/metabolismo , Área Tegmental Ventral/citologíaRESUMEN
Chronic stress causes dysregulations of mood and energy homeostasis, but the neurocircuitry underlying these alterations remain to be fully elucidated. Here we demonstrate that chronic restraint stress in mice results in hyperactivity of pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus (POMCARH neurons) associated with decreased neural activities of dopamine neurons in the ventral tegmental area (DAVTA neurons). We further revealed that POMCARH neurons project to the VTA and provide an inhibitory tone to DAVTA neurons via both direct and indirect neurotransmissions. Finally, we show that photoinhibition of the POMCARHâVTA circuit in mice increases body weight and food intake, and reduces depression-like behaviors and anhedonia in mice exposed to chronic restraint stress. Thus, our results identified a novel neurocircuitry regulating feeding and mood in response to stress.
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Anhedonia , Depresión/metabolismo , Trastornos de Alimentación y de la Ingestión de Alimentos/etiología , Trastornos de Alimentación y de la Ingestión de Alimentos/metabolismo , Vías Nerviosas , Proopiomelanocortina/metabolismo , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/patología , Trastornos de Alimentación y de la Ingestión de Alimentos/psicología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/patologíaRESUMEN
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 Cß 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.
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Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Ácido Succínico/farmacología , Animales , Ciclo del Ácido Cítrico/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Contracción Muscular/efectos de los fármacos , Fatiga Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Cadenas Pesadas de Miosina/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Transducción de Señal/efectos de los fármacosRESUMEN
PURPOSE OF REVIEW: Obesity and diabetes have already become the second largest risk factor for cardiovascular disease. During the last decade, remarkable advances have been made in understanding the human genome's contribution to glucose homeostasis disorders and obesity. A few studies on rare mutations of candidate genes provide potential genetic targets for the treatment of diabetes and obesity. In this review, we discussed the detailed findings of these studies and the possible causalities between specific genetic variations and dysfunctions in energy or glucose homeostasis. We are optimistic that novel therapeutic strategies targeting these specific mutants for treating and preventing diabetes and obesity will be developed in the near future. RECENT FINDINGS: Studies on rare genetic mutation-caused obesity or diabetes have identified potential genetic targets to decrease body weight or reduce the risk of diabetes. Rare mutations observed in lipodystrophy, obese, or diabetic human patients are promising targets in the treatment of diabetes and obesity.
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Glucosa , Obesidad , Peso Corporal , Homeostasis , Humanos , Mutación , Obesidad/genéticaRESUMEN
Skeletal muscle atrophy due to excessive protein degradation is the main cause for muscle dysfunction, fatigue, and weakening of athletic ability. Endurance exercise is effective to attenuate muscle atrophy, but the underlying mechanism has not been fully investigated. α-Ketoglutarate (AKG) is a key intermediate of tricarboxylic acid cycle, which is generated during endurance exercise. Here, we demonstrated that AKG effectively attenuated corticosterone-induced protein degradation and rescued the muscle atrophy and dysfunction in a Duchenne muscular dystrophy mouse model. Interestingly, AKG also inhibited the expression of proline hydroxylase 3 (PHD3), one of the important oxidoreductases expressed under hypoxic conditions. Subsequently, we identified the ß2 adrenergic receptor (ADRB2) as a downstream target for PHD3. We found AKG inhibited PHD3/ADRB2 interaction and therefore increased the stability of ADRB2. In addition, combining pharmacologic and genetic approaches, we showed that AKG rescues skeletal muscle atrophy and protein degradation through a PHD3/ADRB2 mediated mechanism. Taken together, these data reveal a mechanism for inhibitory effects of AKG on muscle atrophy and protein degradation. These findings not only provide a molecular basis for the potential use of exercise-generated metabolite AKG in muscle atrophy treatment, but also identify PHD3 as a potential target for the development of therapies for muscle wasting.-Cai, X., Yuan, Y., Liao, Z., Xing, K., Zhu, C., Xu, Y., Yu, L., Wang, L., Wang, S., Zhu, X., Gao, P., Zhang, Y., Jiang, Q., Xu, P., Shu, G. α-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway.
Asunto(s)
Ácidos Cetoglutáricos/uso terapéutico , Proteínas Musculares/metabolismo , Distrofia Muscular de Duchenne/tratamiento farmacológico , Procolágeno-Prolina Dioxigenasa/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Animales , Corticosterona/farmacología , Modelos Animales de Enfermedad , Masculino , Redes y Vías Metabólicas/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Atrofia Muscular/prevención & control , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/patología , Estabilidad Proteica/efectos de los fármacos , Proteolisis/efectos de los fármacosRESUMEN
BACKGROUND/AIMS: Apolipoprotein A-IV (apoA-IV) in the brain potently suppresses food intake. However, the mechanisms underlying its anorexigenic effects remain to be identified. METHODS: We first examined the effects of apoA-IV on cellular activities in hypothalamic neurons that co-express agouti-related peptide (AgRP) and neuropeptide Y (NPY) and in neurons that express pro-opiomelanocortin (POMC). We then compared anorexigenic effects of apoA-IV in wild-type mice and in mutant mice lacking melanocortin 4 receptors (MC4Rs; the receptors of AgRP and the POMC gene product). Finally, we examined expression of apoA-IV in mouse hypothalamus and quantified its protein levels at fed versus fasted states. RESULTS: We demonstrate that apoA-IV inhibited the firing rate of AgRP/NPY neurons. The decreased firing was associated with hyperpolarized membrane potential and decreased miniature excitatory postsynaptic current. We further used c-fos immunoreactivity to show that intracerebroventricular (i.c.v.) injections of apoA-IV abolished the fasting-induced activation of AgRP/NPY neurons in mice. Further, we found that apoA-IV depolarized POMC neurons and increased their firing rate. In addition, genetic deletion of MC4Rs blocked anorexigenic effects of i.c.v. apoA-IV. Finally, we detected endogenous apoA-IV in multiple neural populations in the mouse hypothalamus, including AgRP/NPY neurons, and food deprivation suppressed hypothalamic apoA-IV protein levels. CONCLUSION: Our findings support a model where central apoA-IV inhibits AgRP/NPY neurons and activates POMC neurons to activate MC4Rs, which in turn suppresses food intake.
Asunto(s)
Apolipoproteína A-V/farmacología , Núcleo Arqueado del Hipotálamo/citología , Regulación de la Expresión Génica/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Proopiomelanocortina/metabolismo , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Animales , Apolipoproteína A-V/metabolismo , Bicuculina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/genética , GABAérgicos/farmacología , Regulación de la Expresión Génica/genética , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuropéptido Y/genética , Neuropéptido Y/metabolismo , Bloqueadores de los Canales de Sodio/farmacología , Tetrodotoxina/farmacología , Valina/análogos & derivados , Valina/farmacologíaRESUMEN
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-HTDRN) 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-HTDRN neurons from naïve male mice had lower baseline firing activity but higher sensitivity to alcohol-induced excitation compared to 5-HTDRN neurons from naïve female mice. Notably, this higher sensitivity was blunted by 17ß-estradiol treatment in males, indicating an estrogen-dependent mechanism. We further showed that both ERα and ERß are expressed in 5-HTDRN neurons, whereas ERα agonist depolarizes and ERß agonist hyperpolarizes 5-HTDRN neurons. Notably, both treatments blocked the stimulatory effects of alcohol on 5-HTDRN 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-HTDRN neurons may contribute to higher levels of binge drinking in females. Consistently, chemogenetic activation of ERα- or ERß-expressing neurons in the DRN reduced binge alcohol drinking. These results support a model in which estrogens act on ERα/ß to prevent alcohol-induced activation of 5-HTDRN neurons, which in return leads to higher binge alcohol drinking.
Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas , Receptor alfa de Estrógeno , Ratones , Femenino , Masculino , Animales , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Núcleo Dorsal del Rafe/metabolismo , Receptor beta de Estrógeno/agonistas , Receptor beta de Estrógeno/metabolismo , Serotonina/metabolismo , Estrógenos/farmacología , Etanol/farmacologíaRESUMEN
There is a regional preference around lymph nodes (LNs) for adipose beiging. Here, we show that local LN removal within inguinal white adipose tissue (iWAT) greatly impairs cold-induced beiging, and this impairment can be restored by injecting M2 macrophages or macrophage-derived C-C motif chemokine (CCL22) into iWAT. CCL22 injection into iWAT effectively promotes iWAT beiging, while blocking CCL22 with antibodies can prevent it. Mechanistically, the CCL22 receptor, C-C motif chemokine receptor 4 (CCR4), within eosinophils and its downstream focal adhesion kinase/p65/interleukin-4 signaling are essential for CCL22-mediated beige adipocyte formation. Moreover, CCL22 levels are inversely correlated with body weight and fat mass in mice and humans. Acute elevation of CCL22 levels effectively prevents diet-induced body weight and fat gain by enhancing adipose beiging. Together, our data identify the CCL22-CCR4 axis as an essential mediator for LN-controlled adaptive thermogenesis and highlight its potential to combat obesity and its associated complications.
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Tejido Adiposo Blanco , Quimiocina CCL22 , Metabolismo Energético , Ganglios Linfáticos , Macrófagos , Termogénesis , Animales , Femenino , Humanos , Masculino , Ratones , Adipocitos Beige/metabolismo , Tejido Adiposo Blanco/metabolismo , Quimiocina CCL22/metabolismo , Eosinófilos/metabolismo , Ganglios Linfáticos/metabolismo , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Obesidad/metabolismo , Receptores CCR4/metabolismo , Transducción de SeñalRESUMEN
Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages that they offer are compromised with aging. Here we show that treating mice with estrogen (E2), a hormone that decreases with age, can counteract the age-related decline in beige adipogenesis when exposed to cold temperature while concurrently enhancing energy expenditure and improving glucose tolerance in mice. Mechanistically, we found that nicotinamide phosphoribosyl transferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related endoplasmic reticulum (ER) stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. Together, our findings shed light on the mechanisms regulating the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT-controlled ER stress pathway as a key regulator of this process.
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Adipocitos Beige , Adipogénesis , Envejecimiento , Estrés del Retículo Endoplásmico , Estrógenos , Nicotinamida Fosforribosiltransferasa , Nicotinamida Fosforribosiltransferasa/metabolismo , Animales , Adipogénesis/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ratones , Envejecimiento/efectos de los fármacos , Envejecimiento/fisiología , Estrógenos/metabolismo , Estrógenos/farmacología , Adipocitos Beige/efectos de los fármacos , Adipocitos Beige/metabolismo , Citocinas/metabolismo , Transducción de Señal/efectos de los fármacos , Femenino , Ratones Endogámicos C57BL , Metabolismo Energético/efectos de los fármacosRESUMEN
Oxysterols are metabolites of cholesterol that regulate cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective estrogen receptor modulator, we hypothesize that 27HC binds to the estrogen receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMCARH) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of POMCARH neurons blocked the anorexigenic effects of 27HC. Mechanistically, we further revealed that 27HC stimulates POMCARH neurons by inhibiting the small conductance of the calcium-activated potassium (SK) channel. Together, our findings suggest that 27HC, through its interaction with ERα and modulation of the SK channel, inhibits food intake as a negative feedback mechanism against a surge in circulating cholesterol.
Asunto(s)
Núcleo Arqueado del Hipotálamo , Receptor alfa de Estrógeno , Conducta Alimentaria , Hidroxicolesteroles , Neuronas , Proopiomelanocortina , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/efectos de los fármacos , Animales , Hidroxicolesteroles/farmacología , Hidroxicolesteroles/metabolismo , Receptor alfa de Estrógeno/metabolismo , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Proopiomelanocortina/metabolismo , Ratones , FemeninoRESUMEN
Eating disorders (EDs) are characterized by severe disturbances in eating behaviors and can sometimes be fatal. Eating disorders are also associated with distressing thoughts and emotions. They can be severe conditions affecting physical, psychological, and social functions. Preoccupation with food, body weight, and shape may also play an important role in the regulation of eating disorders. Common eating disorders have three major types: anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). In some cases, EDs can have serious consequences for an individual's physical and mental health. These disorders often develop during adolescence or early adulthood and affect both males and females, although they are more commonly diagnosed in young adult females. Treatment for EDs typically involves a combination of therapy, nutrition counseling, and medical care. In this narrative review, the authors summarized what is known of EDs and discussed the future directions that may be worth exploring in this emerging area.
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Anorexia Nerviosa , Trastorno por Atracón , Bulimia Nerviosa , Trastornos de Alimentación y de la Ingestión de Alimentos , Masculino , Femenino , Adulto Joven , Adolescente , Humanos , Adulto , Trastornos de Alimentación y de la Ingestión de Alimentos/epidemiología , Trastornos de Alimentación y de la Ingestión de Alimentos/terapia , Bulimia Nerviosa/psicología , Trastorno por Atracón/psicología , Peso CorporalRESUMEN
Asprosin, a recently identified adipokine, activates agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARH) via binding to protein tyrosine phosphatase receptor δ (Ptprd) to increase food intake. However, the intracellular mechanisms responsible for asprosin/Ptprd-mediated activation of AgRPARH neurons remain unknown. Here, we demonstrate that the small-conductance calcium-activated potassium (SK) channel is required for the stimulatory effects of asprosin/Ptprd on AgRPARH neurons. Specifically, we found that deficiency or elevation of circulating asprosin increased or decreased the SK current in AgRPARH neurons, respectively. AgRPARH-specific deletion of SK3 (an SK channel subtype highly expressed in AgRPARH neurons) blocked asprosin-induced AgRPARH activation and overeating. Furthermore, pharmacological blockade, genetic knockdown, or knockout of Ptprd abolished asprosin's effects on the SK current and AgRPARH neuronal activity. Therefore, our results demonstrated an essential asprosin-Ptprd-SK3 mechanism in asprosin-induced AgRPARH activation and hyperphagia, which is a potential therapeutic target for the treatment of obesity.
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Núcleo Arqueado del Hipotálamo , Obesidad , Humanos , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Proteína Relacionada con Agouti/farmacología , Núcleo Arqueado del Hipotálamo/metabolismo , Hipotálamo/metabolismo , Neuronas/metabolismo , Obesidad/metabolismo , Adipoquinas/metabolismo , Fibrilina-1/metabolismoRESUMEN
Long-term ad libitum dietary restrictions, such as low-protein diets (LPDs), improve metabolic health and extend the life span of mice and humans. However, most studies conducted thus far have focused on the preventive effects of LPDs on metabolic syndromes. To test the therapeutic potential of LPD, we treated a lipodystrophy mouse model IR FKO (adipose-specific insulin receptor knockout) in this study. We have previously shown that IR FKO mice have profound insulin resistance, hyperglycemia, and whitenng of interscapular brown adipose tissue (BAT), closely mimicking the phenotypes in lipoatrophic diabetic patients. Here, we demonstrate that 14-day of LPD (5.1% kcal from protein) feeding is sufficient to reduce postprandial blood glucose, improve insulin resistance, and normalize glucose tolerance in the IR FKO mice. This profound metabolic improvement is associated with BAT activation and increase in whole body energy expenditure. To confirm, we showed that surgical denervation of BAT attenuated the beneficial metabolic effects of LPD feeding in IR FKO mice, including the 'browning' effects on BAT and the glucose-ameliorating results. However, BAT denervation failed to affect the body weight-lowering effects of LPD. Together, our results imply a therapeutic potential to use LPD for the treatment of lipoatrophic diabetes.
RESUMEN
Long-term ad libitum dietary restrictions, such as low-protein diets (LPDs), improve metabolic health and extend the life span of mice and humans. However, most studies conducted thus far have focused on the preventive effects of LPDs on metabolic syndromes. To test the therapeutic potential of LPD, we treated a lipodystrophy mouse model IRFKO (adipose-specific insulin receptor knockout) in this study. We have previously shown that IRFKO mice have profound insulin resistance, hyperglycemia, and whitening of interscapular brown adipose tissue (BAT), closely mimicking the phenotypes in lipoatrophic diabetic patients. Here, we demonstrate that 14-day of LPD (5.1% kcal from protein) feeding is sufficient to reduce postprandial blood glucose, improve insulin resistance, and normalize glucose tolerance in the IRFKO mice. This profound metabolic improvement is associated with BAT activation and increase in whole body energy expenditure. To confirm, we showed that surgical denervation of BAT attenuated the beneficial metabolic effects of LPD feeding in IRFKO mice, including the 'browning' effects on BAT and the glucose-ameliorating results. However, BAT denervation failed to affect the body weight-lowering effects of LPD. Together, our results imply a therapeutic potential to use LPD for the treatment of lipoatrophic diabetes.
Asunto(s)
Diabetes Mellitus , Hiperglucemia , Resistencia a la Insulina , Lipodistrofia , Humanos , Animales , Dieta con Restricción de Proteínas , Tejido Adiposo Pardo , Hiperglucemia/complicaciones , Glucosa , Modelos Animales de EnfermedadRESUMEN
Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages they offer are compromised with aging. Here, we show that treating mice with estrogen (E2), a hormone that decreases with age, to mice can counteract the aging- related decline in beige adipocyte formation when subjected to cold, while concurrently enhancing energy expenditure and improving glucose tolerance. Mechanistically, we find that nicotinamide phosphoribosyltranferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related ER stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. In conclusion, our findings shed light on the mechanisms governing the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT controlled ER stress as a key regulator of this process. Highlights: Estrogen restores beige adipocyte failure along with improved energy metabolism in old mice.Estrogen enhances the thermogenic gene program by mitigating age-induced ER stress.Estrogen enhances the beige adipogenesis derived from SMA+ APCs.Inhibiting the NAMPT signaling pathway abolishes estrogen-promoted beige adipogenesis.