Central Melanin-Concentrating Hormone Influences Liver and Adipose Metabolism Via Specific Hypothalamic Nuclei and Efferent Autonomic/JNK1 Pathways

Imbernón, Mónica; Beiroa, Daniel; Vázquez, María J.; Morgan, Donald A.; Veyrat-Durebex, Christelle; Porteiro, Begoña; Díaz-Arteaga, Adenis; Senra, Ana; Busquets, Sı́lvia; Velásquez, Douglas A; Al‐Massadi, Omar; Varela, Luis; Gándara, Marina; López-Soriano, Francisco-Javier; Gallego, Rosalı́a; Seoane, Luísa M.; Argilés, Josep M.; López, Miguel; Davis, Roger J.; Sabio, Guadalupe; Rohner‐Jeanrenaud, Françoise; Rahmouni, Kamal; Diéguez, Carlos; Nogueiras, Rubén

doi:10.1053/j.gastro.2012.10.051

Cited by 80 publications

(104 citation statements)

References 52 publications

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“…Intracerebroventricular (ICV) cannulae were implanted stereotaxically in mice and rats, as described previously (22). Animals received vehicle, GLP-1 (1 mg/mouse), liraglutide (3 mg/mouse or 10 mg/rat), or AICAR (3 mg/mouse).…”

Section: Implantation Of Intracerebroventricular Cannulae and Treatmentsmentioning

confidence: 99%

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GLP-1 Agonism Stimulates Brown Adipose Tissue Thermogenesis and Browning Through Hypothalamic AMPK

et al. 2014

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GLP-1 receptor (GLP-1R) is widely located throughout the brain, but the precise molecular mechanisms mediating the actions of GLP-1 and its long-acting analogs on adipose tissue as well as the brain areas responsible for these interactions remain largely unknown. We found that central injection of a clinically used GLP-1R agonist, liraglutide, in mice stimulates brown adipose tissue (BAT) thermogenesis and adipocyte browning independent of nutrient intake. The mechanism controlling these actions is located in the hypothalamic ventromedial nucleus (VMH), and the activation of AMPK in this area is sufficient to blunt both central liraglutide-induced thermogenesis and adipocyte browning. The decreased body weight caused by the central injection of liraglutide in other hypothalamic sites was sufficiently explained by the suppression of food intake. In a longitudinal study involving obese type 2 diabetic patients treated for 1 year with GLP-1R agonists, both exenatide and liraglutide increased energy expenditure. Although the results do not exclude the possibility that extrahypothalamic areas are also modulating the effects of GLP-1R agonists, the data indicate that long-acting GLP-1R agonists influence body weight by regulating either food intake or energy expenditure through various hypothalamic sites and that these mechanisms might be clinically relevant.

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Section: Implantation Of Intracerebroventricular Cannulae and Treatmentsmentioning

confidence: 99%

“…Rat brains were fixed, and diaminobenzidine immunohistochemistry and detection of GFP were performed as previously reported (22,25).…”

Section: Immunohistochemistry and Immunofluorescencementioning

confidence: 99%

GLP-1 Agonism Stimulates Brown Adipose Tissue Thermogenesis and Browning Through Hypothalamic AMPK

et al. 2014

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“…For peripheral treatments, mice received an intraperitoneal administration of UGN (25 mg/mouse). Surgical vagotomy (VGX) was performed as previously described (17,18). Under ketamine-xylazine anesthesia, mice were placed on their backs, and a midline abdominal incision was made.…”

Section: Treatments and Surgeriesmentioning

confidence: 99%

“…RNA was isolated from the adipose tissue using TRIzol Reagent (Invitrogen, Carlsbad, CA) according to the manufacturer's instructions (18). The extracted total RNA was purified with DNase treatment using a DNAfree kit as a template (Ambion; Thermo Fisher Scientific, Grand Island, NY) to generate first-strand cDNAs using a High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA).…”

Section: Real-time Pcrmentioning

confidence: 99%

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Uroguanylin Action in the Brain Reduces Weight Gain in Obese Mice via Different Efferent Autonomic Pathways

et al. 2015

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The gut-brain axis is of great importance in the control of energy homeostasis. The identification of uroguanylin (UGN), a peptide released in the intestines that is regulated by nutritional status and anorectic actions, as the endogenous ligand for the guanylyl cyclase 2C receptor has revealed a new system in the regulation of energy balance. We show that chronic central infusion of UGN reduces weight gain and adiposity in diet-induced obese mice. These effects were independent of food intake and involved specific efferent autonomic pathways. On one hand, brain UGN induces brown adipose tissue thermogenesis, as well as browning and lipid mobilization in white adipose tissue through stimulation of the sympathetic nervous system. On the other hand, brain UGN augments fecal output through the vagus nerve. These findings are of relevance as they suggest that the beneficial metabolic actions of UGN through the sympathetic nervous system do not involve nondesirable gastrointestinal adverse effects, such as diarrhea. The present work provides mechanistic insights into how UGN influences energy homeostasis and suggests that UGN action in the brain represents a feasible pharmacological target in the treatment of obesity.After the ingestion of a meal, the presence of nutrients in the gastrointestinal (GI) tract initiates complex neural and hormonal responses that send signals to the brain about the ongoing changes in nutritional status. Among the different strategies used to communicate to the brain, the gut secretes peptides that reach the central nervous system (CNS) via afferent nerve fibers or the circulation (1,2). New gut hormones are continuously discovered, and, with the exception of ghrelin, which is the only peptidic hormone favoring weight gain and adiposity, all of them are associated with a negative energy balance and are thus potential targets for the treatment of obesity (3,4).One of the most recently discovered gut hormones is uroguanylin (UGN), a 16-amino acid peptide secreted mainly from duodenal epithelial cells. UGN is synthesized as a prohormone (pro-UGN), which, after cleavage by a still unknown enzyme, is converted to the active UGN (3,5). Both pro-UGN and UGN activate the guanilate cyclase 2C receptor (GUCY2C), which is also targeted by diarrheagenic bacterial heat-stable enterotoxins (STs) (6). The activation of GUCY2C leads to elevated intracellular levels of cyclic guanosine monophosphate (7), which in invertebrate species has been demonstrated to lead to alterations in food behavior and energy-balance regulation (8,9). Circulating UGN levels were decreased in fasted and leptin-deficient mice but recovered after refeeding or exogenous leptin

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Targeting MCH Neuroendocrine Circuit in Lateral Hypothalamus to Protect Against Skeletal Senescence

Guo,

Zhu,

et al. 2024

Advanced Science

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Neuroendocrine regulation is essential for maintaining metabolic homeostasis. However, whether neuroendocrine pathway influence bone metabolism and skeletal senescence is unelucidated. Here, a central neuroendocrine circuit is identified that directly controls osteogenesis. Using virus based tracing, this study is identified that melanin concentrating hormone (MCH) expressing neurons in the lateral hypothalamus (LH) are connected to the bone. Chemogenetic activation of MCH neurons in the LH induces osteogenesis, whereas inhibiting these neurons reduces osteogenesis. Meanwhile, MCH is released into the circulation upon chemogenetic activation of these neurons. Single cell sequencing reveals that blocking MCH neurons in the LH diminishes osteogenic differentiation of bone marrow stromal cells (BMSCs) and induces senescence. Mechanistically, MCH promotes BMSC differentiation by activating MCHR1 via PKA signaling, and activating MCHR1 by MCH agonists attenuate skeletal senescence in mice. By elucidating a brain‐bone connection that autonomously enhances osteogenesis, these findings uncover the neuroendocrinological mechanisms governing bone mass regulation and protect against skeletal senescence.

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Central Melanin-Concentrating Hormone Influences Liver and Adipose Metabolism Via Specific Hypothalamic Nuclei and Efferent Autonomic/JNK1 Pathways

Cited by 80 publications

References 52 publications

GLP-1 Agonism Stimulates Brown Adipose Tissue Thermogenesis and Browning Through Hypothalamic AMPK

GLP-1 Agonism Stimulates Brown Adipose Tissue Thermogenesis and Browning Through Hypothalamic AMPK

Uroguanylin Action in the Brain Reduces Weight Gain in Obese Mice via Different Efferent Autonomic Pathways

Targeting MCH Neuroendocrine Circuit in Lateral Hypothalamus to Protect Against Skeletal Senescence

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