Deciphering an AgRP-serotoninergic neural circuit in distinct control of energy metabolism from feeding

AbstractContrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energy expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4RdlDRN neurons integrate pre-synaptic AgRP signaling, thereby modulating the post-synaptic serotonergic pathway. Specifically, the MC4RdlDRN signaling elicits profound, bi-directional, regulation of body weight mainly through sympathetic outflow that reprograms mitochondrial bioenergetics within brown and beige fat while feeding remains intact. Together, we suggest that this AgRP neural circuit plays a unique role in persistent control of energy expenditure and body weight, hinting next-generation therapeutic approaches for obesity and metabolic disorders.

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AgRP(83–132) Acts as an Inverse Agonist on the Human-Melanocortin-4 Receptor

Molecular Endocrinology ◽

10.1210/mend.15.1.0578 ◽

2001 ◽

Vol 15 (1) ◽

pp. 164-171 ◽

Cited By ~ 17

Author(s):

Wouter A. J. Nijenhuis ◽

Julia Oosterom ◽

Roger A. H. Adan

Keyword(s):

Body Weight ◽

Adenylyl Cyclase ◽

Inverse Agonist ◽

Constitutive Activity ◽

Related Protein ◽

Melanocortin System ◽

Receptor Level ◽

Melanocortin 4 Receptor ◽

Agouti Related Protein

Abstract The central melanocortin (MC) system has been demonstrated to act downstream of leptin in the regulation of body weight. The system comprises α-MSH, which acts as agonist, and agouti-related protein (AgRP), which acts as antagonist at the MC3 and MC4 receptors (MC3R and MC4R). This property suggests that MCR activity is tightly regulated and that opposing signals are integrated at the receptor level. We here propose another level of regulation within the melanocortin system by showing that the human (h) MC4R displays constitutive activity in vitro as assayed by adenylyl cyclase (AC) activity. Furthermore, human AgRP(83–132) acts as an inverse agonist for the hMC4R since it was able to suppress constitutive activity of the hMC4R both in intact B16/G4F melanoma cells and membrane preparations. The effect of AgRP(83–132) on the hMC4R was blocked by the MC4R ligand SHU9119. Also the hMC3R and the mouse(m)MC5R were shown to be constitutively active. AgRP(83–132) acted as an inverse agonist on the hMC3R but not on the mMC5R. Thus, AgRP is able to regulate MCR activity independently of α-MSH. These findings form a basis to further investigate the relevance of constitutive activity of the MC4R and of inverse agonism of AgRP for the regulation of body weight.

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Physical Activity, Energy Expenditure, and Defense of Body Weight in Melanocortin 4 Receptor-Deficient Male Rats

Scientific Reports ◽

10.1038/srep37435 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 6

Author(s):

Tariq I. Almundarij ◽

Mark E. Smyers ◽

Addison Spriggs ◽

Lydia A. Heemstra ◽

Lisa Beltz ◽

...

Keyword(s):

Physical Activity ◽

Body Weight ◽

Energy Expenditure ◽

Male Rats ◽

Physical Activity Energy Expenditure ◽

Melanocortin 4 Receptor ◽

Activity Energy

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Author Correction: Physical Activity, Energy Expenditure, and Defense of Body Weight in Melanocortin 4 Receptor-Deficient Male Rats

Scientific Reports ◽

10.1038/s41598-019-42850-2 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Tariq I. Almundarij ◽

Mark E. Smyers ◽

Addison Spriggs ◽

Lydia A. Heemstra ◽

Lisa Beltz ◽

...

Keyword(s):

Physical Activity ◽

Body Weight ◽

Energy Expenditure ◽

Male Rats ◽

Physical Activity Energy Expenditure ◽

Melanocortin 4 Receptor ◽

Activity Energy

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Reciprocal control of obesity and anxiety–depressive disorder via a GABA and serotonin neural circuit

Molecular Psychiatry ◽

10.1038/s41380-021-01053-w ◽

2021 ◽

Author(s):

Guobin Xia ◽

Yong Han ◽

Fantao Meng ◽

Yanlin He ◽

Dollada Srisai ◽

...

Keyword(s):

Neural Circuit ◽

Combined Treatment ◽

Neural Mechanism ◽

Mental States ◽

Genetic Enhancement ◽

Anxiety And Depression ◽

Calorie Intake ◽

Bed Nucleus ◽

Low Fat Diet ◽

Melanocortin 4 Receptor

AbstractThe high comorbidity between obesity and mental disorders, such as depression and anxiety, often exacerbates metabolic and neurological symptoms significantly. However, neural mechanisms that underlie reciprocal control of feeding and mental states are largely elusive. Here we report that melanocortin 4 receptor (MC4R) neurons located in the dorsal bed nucleus of the stria terminus (dBNST) engage in the regulation of mentally associated weight gain by receiving GABAergic projections from hypothalamic AgRP neurons onto α5-containing GABAA receptors and serotonergic afferents onto 5-HT3 receptors. Chronic treatment with a high-fat diet (HFD) significantly blunts the hyperexcitability of AgRP neurons in response to not only hunger but also anxiety and depression-like stimuli. Such HFD-mediated desensitization reduces GABAergic outputs from AgRP neurons to downstream MC4RdBNST neurons, resulting in severe mental dysregulation. Genetic enhancement of the GABAAR-α5 or suppression of the 5-HT3R within the MC4RdBNST neurons not only abolishes HFD-induced anxiety and depression but also robustly reduces body weight by suppression of food intake. To gain further translational insights, we revealed that combined treatment of zonisamide (enhancing the GABAAR-α5 signaling) and granisetron (a selective 5-HT3R antagonist) alleviates mental dysfunction and yields a robust reversal of diet-induced obesity by reducing total calorie intake and altering food preference towards a healthy low-fat diet. Our results unveil a neural mechanism for reciprocal control of appetite and mental states, which culminates in a novel zonisamide-granisetron cocktail therapy for potential tackling the psychosis-obesity comorbidity.

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Effect of raw and encapsulated policosanol on lipid profiles, blood biochemistry, activity, energy expenditure and macronutrient metabolism of adult cats

Journal of Feline Medicine and Surgery ◽

10.1177/1098612x211013738 ◽

2021 ◽

pp. 1098612X2110137

Author(s):

James R Templeman ◽

Kylie Hogan ◽

Alexandra Blanchard ◽

Christopher PF Marinangeli ◽

Alexandra Camara ◽

...

Keyword(s):

Body Weight ◽

Energy Expenditure ◽

Indirect Calorimetry ◽

Respiratory Quotient ◽

Blood Count ◽

Complete Blood Count ◽

Serum Biochemistry ◽

Blood Collection ◽

Adult Cats ◽

Activity Energy

Objectives The objective of this study was to verify the safety of policosanol supplementation for domestic cats. The effects of raw and encapsulated policosanol were compared with positive (L-carnitine) and negative (no supplementation) controls on outcomes of complete blood count, serum biochemistry, energy expenditure, respiratory quotient and physical activity in healthy young adult cats. Methods The study was a replicated 4 × 4 complete Latin square design. Eight cats (four castrated males, four spayed females; mean age 3.0 ± 1.0 years; mean weight 4.36 ± 1.08 kg; mean body condition score 5.4 ± 1.4) were blocked by sex and body weight then randomized to treatment groups: raw policosanol (10 mg/kg body weight), encapsulated policosanol (50 mg/kg body weight), L-carnitine (200 mg/kg body weight) or no supplementation. Treatments were supplemented to a basal diet for 28 days with a 1-week washout between periods. Food was distributed equally between two offerings to ensure complete supplement consumption (first offering) and measure consumption time (second offering). Blood collection (lipid profile, complete blood count, serum biochemistry) and indirect calorimetry (energy expenditure, respiratory quotient) were conducted at days 0, 14 and 28 of each period. Activity monitors were worn 7 days prior to indirect calorimetry and blood collection. Data were analyzed using a repeated measures mixed model (SAS, v.9.4). Results Food intake and body weight were similar among treatments. There was no effect of treatment on lipid profile, serum biochemistry, activity, energy expenditure or respiratory quotient ( P >0.05); however, time to consume a second meal was greatest in cats fed raw policosanol ( P <0.05). Conclusions and relevance These data suggest that policosanol is safe for feline consumption. Further studies with cats demonstrating cardiometabolic risk factors are warranted to confirm whether policosanol therapy is an efficacious treatment for hyperlipidemia and obesity.

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Metabolic, gastrointestinal, and CNS neuropeptide effects of brain leptin administration in the rat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1999.276.5.r1425 ◽

1999 ◽

Vol 276 (5) ◽

pp. R1425-R1433 ◽

Cited By ~ 4

Author(s):

Gertjan van Dijk ◽

Randy J. Seeley ◽

Todd E. Thiele ◽

Mark I. Friedman ◽

Hong Ji ◽

...

Keyword(s):

Fatty Acids ◽

Body Weight ◽

Energy Expenditure ◽

Neuropeptide Y ◽

Caloric Restriction ◽

Resting Energy Expenditure ◽

Corticotropin Releasing Hormone ◽

Plasma Fatty Acids ◽

The Third ◽

Ad Libitum

To investigate whether brain leptin involves neuropeptidergic pathways influencing ingestion, metabolism, and gastrointestinal functioning, leptin (3.5 μg) was infused daily into the third cerebral ventricular of rats for 3 days. To distinguish between direct leptin effects and those secondary to leptin-induced anorexia, we studied vehicle-infused rats with food available ad libitum and those that were pair-fed to leptin-treated animals. Although body weight was comparably reduced (−8%) and plasma glycerol was comparably increased (142 and 17%, respectively) in leptin-treated and pair-fed animals relative to controls, increases in plasma fatty acids and ketones were only detected (132 and 234%, respectively) in pair-fed rats. Resting energy expenditure (−15%) and gastrointestinal fill (−50%) were reduced by pair-feeding relative to the ad libitum group, but they were not reduced by leptin treatment. Relative to controls, leptin increased hypothalamic mRNA for corticotropin-releasing hormone (CRH; 61%) and for proopiomelanocortin (POMC; 31%) but did not reduce mRNA for neuropeptide Y. These results suggest that CNS leptin prevents metabolic/gastrointestinal responses to caloric restriction by activating hypothalamic CRH- and POMC-containing pathways and raise the possibility that these peripheral responses to CNS leptin administration contribute to leptin’s anorexigenic action.

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Effect of adrenaline infusion on fatty acid and glucose turnover in lean and obese human subjects in the post-absorptive and fed states

Clinical Science ◽

10.1042/cs0810635 ◽

1991 ◽

Vol 81 (5) ◽

pp. 635-644 ◽

Cited By ~ 31

Author(s):

Alan A. Connacher ◽

William M. Bennet ◽

Roland T. Jung ◽

Dennis M. Bier ◽

Christopher C. T. Smith ◽

...

Keyword(s):

Body Weight ◽

Energy Expenditure ◽

Human Subjects ◽

Ideal Body Weight ◽

Glycerol Release ◽

Fed State ◽

Adrenaline Infusion ◽

Obese Subjects ◽

Ideal Body ◽

Obese Human

1. Energy expenditure, plasma glucose and palmitate kinetics and leg glycerol release were determined simultaneously both before and during adrenaline infusion in lean and obese human subjects. Seven lean subjects (mean 96.5% of ideal body weight) were studied in the post-absorptive state and also during mixed nutrient liquid feeding, eight obese subjects (mean 165% of ideal body weight) were studied in the post-absorptive state and six obese subjects (mean 174% of ideal body weight) were studied during feeding. 2. Resting energy expenditure was higher in the obese subjects, but the thermic response to adrenaline, both in absolute and percentage terms, was similar in lean and obese subjects. Plasma adrenaline concentrations attained (3 nmol/l) were comparable in all groups and the infusion had no differential effects on the plasma insulin concentration. Before adrenaline infusion the plasma glucose flux was higher in the obese than in the lean subjects in the fed state only (45.8 ± 3.8 versus 36.6 ± 1.0 mmol/h, P <0.05); it increased to the same extent in both groups with the adrenaline infusion. 3. Before the adrenaline infusion plasma palmitate flux was higher in the obese than in the lean subjects (by 51%, P <0.01, in the post-absorptive state and by 78%, P <0.05, in the fed state). However, there was no significant change during adrenaline infusion in the obese subjects (from 13.5 ± 1.00 to 15.0 ± 1.84 mmol/h, not significant, in the post-absorptive state and from 14.4 ± 2.13 to 15.7 ± 1.74 mmol/h, not significant, in the fed state), whereas there were increases in the lean subjects (from 8.93 ± 1.10 to 11.2 ± 1.19 mmol/h, P <0.05, in the post-absorptive state, and from 8.06 ± 1.19 to 9.86 ± 0.93 mmol/h, P <0.05, in the fed state). 4. Before adrenaline infusion the palmitate oxidation rate was also higher in the obese than in the lean subjects (1.86 ± 0.14 versus 1.22 ± .09 mmol/h, P <0.01, in the post-absorptive state and 1,73 ± 0.25 versus 1.12 ± 0.12 mmol/h, P <0.05, in the fed state). However, in response to adrenaline the fractional oxidation rate (% of flux) increased less in the obese than in the lean subjects, especially in the post-absorptive state (from 13.8 ± 1.02 to 14.9 ± 1.39%, not significant, versus from 13.7 ± 0.98 to 19.3 ± 1.92%, P <0.05). These effects were independent of feeding. Leg glycerol release increased more in the lean subjects with adrenaline infusion, although increases in the plasma glycerol concentration did not differ between the groups. 5. These results suggest that in obese subjects plasma inter-organ transport of fatty acids and the subsequent fractional oxidation responses favour storage of triacylglycerol. These factors may be important determinants for the development and maintenance of the obese state.

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Neither Agouti-Related Protein nor Neuropeptide Y Is Critically Required for the Regulation of Energy Homeostasis in Mice

Molecular and Cellular Biology ◽

10.1128/mcb.22.14.5027-5035.2002 ◽

2002 ◽

Vol 22 (14) ◽

pp. 5027-5035 ◽

Cited By ~ 296

Author(s):

Su Qian ◽

Howard Chen ◽

Drew Weingarth ◽

Myrna E. Trumbauer ◽

Dawn E. Novi ◽

...

Keyword(s):

Body Weight ◽

Neuropeptide Y ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Body Weight Gain ◽

Physiological Role ◽

Related Protein ◽

Double Knockout ◽

Orexigenic Peptide ◽

Agouti Related Protein

ABSTRACT Agouti-related protein (AgRP), a neuropeptide abundantly expressed in the arcuate nucleus of the hypothalamus, potently stimulates feeding and body weight gain in rodents. AgRP is believed to exert its effects through the blockade of signaling by α-melanocyte-stimulating hormone at central nervous system (CNS) melanocortin-3 receptor (Mc3r) and Mc4r. We generated AgRP-deficient (Agrp−/− ) mice to examine the physiological role of AgRP. Agrp−/− mice are viable and exhibit normal locomotor activity, growth rates, body composition, and food intake. Additionally, Agrp−/− mice display normal responses to starvation, diet-induced obesity, and the administration of exogenous leptin or neuropeptide Y (NPY). In situ hybridization failed to detect altered CNS expression levels for proopiomelanocortin, Mc3r, Mc4r, or NPY mRNAs in Agrp−/− mice. As AgRP and the orexigenic peptide NPY are coexpressed in neurons of the arcuate nucleus, we generated AgRP and NPY double-knockout (Agrp−/− ;Npy−/− ) mice to determine whether NPY or AgRP plays a compensatory role in Agrp−/− or NPY-deficient (Npy−/− ) mice, respectively. Similarly to mice deficient in either AgRP or NPY, Agrp−/− ;Npy−/− mice suffer no obvious feeding or body weight deficits and maintain a normal response to starvation. Our results demonstrate that neither AgRP nor NPY is a critically required orexigenic factor, suggesting that other pathways capable of regulating energy homeostasis can compensate for the loss of both AgRP and NPY.

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Severe protein deficiency induces hepatic expression and systemic level of FGF21 but inhibits its hypothalamic expression in growing rats

Scientific Reports ◽

10.1038/s41598-021-91274-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Joanna Moro ◽

Catherine Chaumontet ◽

Patrick C. Even ◽

Anne Blais ◽

Julien Piedcoq ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Energy Expenditure ◽

Energy Intake ◽

Dietary Protein ◽

Protein Deficiency ◽

Protein Diet ◽

Growing Rats ◽

Low Protein ◽

Protein Diets

AbstractTo study, in young growing rats, the consequences of different levels of dietary protein deficiency on food intake, body weight, body composition, and energy balance and to assess the role of FGF21 in the adaptation to a low protein diet. Thirty-six weanling rats were fed diets containing 3%, 5%, 8%, 12%, 15% and 20% protein for three weeks. Body weight, food intake, energy expenditure and metabolic parameters were followed throughout this period. The very low-protein diets (3% and 5%) induced a large decrease in body weight gain and an increase in energy intake relative to body mass. No gain in fat mass was observed because energy expenditure increased in proportion to energy intake. As expected, Fgf21 expression in the liver and plasma FGF21 increased with low-protein diets, but Fgf21 expression in the hypothalamus decreased. Under low protein diets (3% and 5%), the increase in liver Fgf21 and the decrease of Fgf21 in the hypothalamus induced an increase in energy expenditure and the decrease in the satiety signal responsible for hyperphagia. Our results highlight that when dietary protein decreases below 8%, the liver detects the low protein diet and responds by activating synthesis and secretion of FGF21 in order to activate an endocrine signal that induces metabolic adaptation. The hypothalamus, in comparison, responds to protein deficiency when dietary protein decreases below 5%.

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