Discrete TrkB-expressing neurons of the dorsomedial hypothalamus regulate feeding and thermogenesis

AbstractMutations in the TrkB neurotrophin receptor lead to profound obesity in humans, and expression of TrkB in the dorsomedial hypothalamus (DMH) is critical for maintaining energy homeostasis. However, the functional implications of TrkB-expressing neurons in the DMH (DMHTrkB) on energy expenditure are unclear. Additionally, the neurocircuitry underlying the effect of DMHTrkB neurons on energy homeostasis has not been explored. In this study, we show that activation of DMHTrkB neurons leads to a robust increase in adaptive thermogenesis and energy expenditure without altering heart rate or blood pressure, while silencing DMHTrkB neurons impairs thermogenesis. Furthermore, we reveal neuroanatomically and functionally distinct populations of DMHTrkB neurons that regulate food intake or thermogenesis. Activation of DMHTrkB neurons projecting to the raphe pallidus stimulates thermogenesis and increased energy expenditure, whereas DMHTrkB neurons that send collaterals to the paraventricular hypothalamus and preoptic area inhibit feeding. Together, our findings provide evidence that DMHTrkB neuronal activity plays an important role in regulating energy expenditure and delineate distinct neurocircuits that underly the separate effects of DMHTrkB neuronal activity on food intake and thermogenesis.Brief summaryThis study shows that TrkB-expressing DMH neurons stimulate thermogenesis through projection to raphe pallidus, while inhibiting feeding through collaterals to paraventricular hypothalamus and preoptic area.

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Discrete TrkB-expressing neurons of the dorsomedial hypothalamus regulate feeding and thermogenesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2017218118 ◽

2021 ◽

Vol 118 (4) ◽

pp. e2017218118

Author(s):

Jessica Houtz ◽

Guey-Ying Liao ◽

Juan Ji An ◽

Baoji Xu

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Neuronal Activity ◽

Energy Homeostasis ◽

Neurotrophin Receptor ◽

Dorsomedial Hypothalamus ◽

Adaptive Thermogenesis ◽

Functional Implications ◽

Regulate Food Intake ◽

Raphe Pallidus

Mutations in the TrkB neurotrophin receptor lead to profound obesity in humans, and expression of TrkB in the dorsomedial hypothalamus (DMH) is critical for maintaining energy homeostasis. However, the functional implications of TrkB-fexpressing neurons in the DMH (DMHTrkB) on energy expenditure are unclear. Additionally, the neurocircuitry underlying the effect of DMHTrkB neurons on energy homeostasis has not been explored. In this study, we show that activation of DMHTrkB neurons leads to a robust increase in adaptive thermogenesis and energy expenditure without altering heart rate or blood pressure, while silencing DMHTrkB neurons impairs thermogenesis. Furthermore, we reveal neuroanatomically and functionally distinct populations of DMHTrkB neurons that regulate food intake or thermogenesis. Activation of DMHTrkB neurons projecting to the raphe pallidus (RPa) stimulates thermogenesis and increased energy expenditure, whereas DMHTrkB neurons that send collaterals to the paraventricular hypothalamus (PVH) and preoptic area (POA) inhibit feeding. Together, our findings provide evidence that DMHTrkB neuronal activity plays an important role in regulating energy expenditure and delineate distinct neurocircuits that underly the separate effects of DMHTrkB neuronal activity on food intake and thermogenesis.

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Gqα/G11α deficiency in dorsomedial hypothalamus leads to obesity resulting from decreased energy expenditure and impaired sympathetic nerve activity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00059.2020 ◽

2020 ◽

Author(s):

Eric A. Wilson ◽

Hui Sun ◽

Zhenzhong Cui ◽

Marshal T. Jahnke ◽

Mritunjay Pandey ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Food Intake ◽

Energy Expenditure ◽

Energy Homeostasis ◽

Dorsomedial Hypothalamus ◽

Ambient Temperatures ◽

Brown Adipose ◽

Inhibit Food Intake ◽

Specific Deletion

The G protein subunits Gqα and G11α (Gq/11α) couple receptors to phospholipase C, leading to increased intracellular calcium. In this study we investigated the consequences of Gq/11α deficiency in the dorsomedial hypothalamus (DMH), a critical site for the control of energy homeostasis. Mice with DMH-specific deletion of Gq/11α (DMHGq/11KO) were generated by stereotaxic injection of AAV-Cre-GFP into the DMH of Gqαflox/flox:G11α-/- mice. Compared to control mice that received DMH injection of AAV-GFP, DMHGq/11KO mice developed obesity associated with reduced energy expenditure without significant changes in food intake or physical activity. DMHGq/11KO mice showed no defects in the ability of the melanocortin agonist melanotan II to acutely stimulate energy expenditure or to inhibit food intake. At room temperature (22oC) DMHGq/11KO mice showed reduced sympathetic nervous system activity in brown adipose tissue (BAT) and heart, accompanied with decreased basal BAT Ucp1 gene expression and lower heart rates. These mice were cold intolerant when acutely exposed to cold (6oC for 5 hours) and had decreased cold-stimulated BAT Ucp1 gene expression. DMHGq/11KO mice also failed to adapt to gradually declining ambient temperatures and to develop adipocyte browning in inguinal white adipose tissue although their BAT Ucp1 was proportionally stimulated. Consistent with impaired cold-induced thermogenesis, the onset of obesity in DMHGq/11KO mice was significantly delayed when housed under thermoneutral conditions (30ºC). Thus, our results show that Gqα and G11α in the DMH are required for the control of energy homeostasis by stimulating energy expenditure and thermoregulation.

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Endocrine factors in the hypothalamic regulation of food intake in females: a review of the physiological roles and interactions of ghrelin, leptin, thyroid hormones, oestrogen and insulin

Nutrition Research Reviews ◽

10.1017/s0954422411000035 ◽

2011 ◽

Vol 24 (1) ◽

pp. 132-154 ◽

Cited By ~ 12

Author(s):

V. Somogyi ◽

A. Gyorffy ◽

T. J. Scalise ◽

D. S. Kiss ◽

G. Goszleth ◽

...

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Thyroid Hormones ◽

Energy Homeostasis ◽

The Body ◽

Feedback Information ◽

Hypothalamic Regulation ◽

The Individual ◽

Desire To Eat ◽

The Brain

Controlling energy homeostasis involves modulating the desire to eat and regulating energy expenditure. The controlling machinery includes a complex interplay of hormones secreted at various peripheral endocrine endpoints, such as the gastrointestinal tract, the adipose tissue, thyroid gland and thyroid hormone-exporting organs, the ovary and the pancreas, and, last but not least, the brain itself. The peripheral hormones that are the focus of the present review (ghrelin, leptin, thyroid hormones, oestrogen and insulin) play integrated regulatory roles in and provide feedback information on the nutritional and energetic status of the body. As peripheral signals, these hormones modulate central pathways in the brain, including the hypothalamus, to influence food intake, energy expenditure and to maintain energy homeostasis. Since the growth of the literature on the role of various hormones in the regulation of energy homeostasis shows a remarkable and dynamic expansion, it is now becoming increasingly difficult to understand the individual and interactive roles of hormonal mechanisms in their true complexity. Therefore, our goal is to review, in the context of general physiology, the roles of the five best-known peripheral trophic hormones (ghrelin, leptin, thyroid hormones, oestrogen and insulin, respectively) and discuss their interactions in the hypothalamic regulation of food intake.

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Oxytocin Secretion Is Related to Measures of Energy Homeostasis in Young Amenorrheic Athletes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2013-4136 ◽

2014 ◽

Vol 99 (5) ◽

pp. E881-E885 ◽

Cited By ~ 29

Author(s):

Elizabeth A. Lawson ◽

Kathryn E. Ackerman ◽

Meghan Slattery ◽

Dean A. Marengi ◽

Hannah Clarke ◽

...

Keyword(s):

Body Mass Index ◽

Growth Factor ◽

Food Intake ◽

Energy Expenditure ◽

Energy Homeostasis ◽

Female Athletes ◽

Young Female ◽

Fibroblast Growth Factor 21 ◽

Energy Availability ◽

Fibroblast Growth

Context: Oxytocin has been implicated in the modulation of energy metabolism in animals. Oxytocin knockout mice develop obesity without a change in food intake, suggesting that a lack of oxytocin may reduce metabolic rate. Furthermore, administration of oxytocin centrally reduces food intake in rats, an effect reversed by an oxytocin antagonist, implying that oxytocin may regulate appetite and energy intake. We have previously demonstrated that young female athletes (in a higher energy expenditure state than nonathletes) have low nocturnal oxytocin compared with nonathletes. Whether oxytocin is associated with measures of energy homeostasis in athletes is unknown. Objective: We hypothesized that oxytocin, a signal for energy availability, would be associated with other measures of energy homeostasis in young female athletes. Design and Setting: We performed a cross-sectional study of 45 females, aged 14–21 years [15 amenorrheic athletes (AA), 15 eumenorrheic athletes, and 15 nonathletes] of comparable body mass index. Methods: Dual x-ray absorptiometry was performed to assess body composition. Indirect calorimetry was used to measure resting energy expenditure (REE). Fasting levels of oxytocin, energy homeostasis hormones irisin and fibroblast growth factor-21, and appetite-regulating hormone peptide YY were obtained. Results: In AA, oxytocin secretion was positively correlated with surrogate measures of energy availability, including weight (r = 0.65, P = .009) and body mass index (r = 0.61, P = .016). Furthermore, oxytocin was associated with REE (r = 0.80, P = .0003), independent of lean mass, and with irisin (r = 0.74, P = .002) and fibroblast growth factor-21 (r = 0.58, P = .024). In eumenorrheic athletes, oxytocin was associated with REE (r = 0.59, P = .021), independent of lean mass. In nonathletes, oxytocin secretion was not significantly associated with measures of energy homeostasis. Conclusions: In AA, oxytocin secretion is associated with measures of energy availability and expenditure, suggesting that oxytocin may be involved in regulation of energy balance in energy deficient states. Further studies determining the role of oxytocin in appetite and energy homeostasis in athletes are warranted.

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PDK1-Foxo1 in Agouti-Related Peptide Neurons Regulates Energy Homeostasis by Modulating Food Intake and Energy Expenditure

PLoS ONE ◽

10.1371/journal.pone.0018324 ◽

2011 ◽

Vol 6 (4) ◽

pp. e18324 ◽

Cited By ~ 28

Author(s):

Yongheng Cao ◽

Masanori Nakata ◽

Shiki Okamoto ◽

Eisuke Takano ◽

Toshihiko Yada ◽

...

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Energy Homeostasis ◽

Related Peptide

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STAT3 but Not ERK2 Is a Crucial Mediator Against Diet-Induced Obesity via VMH Neurons

10.2337/figshare.14448147 ◽

2021 ◽

Author(s):

Gabriel Henrique Marques Gonçalves ◽

Sabrina Mara Tristão ◽

Rafaella Eduarda Volpi ◽

Gislaine Almeida-Pereira ◽

Beatriz de Carvalho Borges ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Energy Expenditure ◽

Energy Homeostasis ◽

Specific Pattern ◽

Conditional Knockout ◽

Steroidogenic Factor 1 ◽

Diet Induced Obesity ◽

Affect Body Weight

Leptin plays an important role in the protection against diet-induced obesity (DIO) by its actions in ventromedial hypothalamic (VMH) neurons. However, little is known about the intracellular mechanisms involved in these effects. To assess the role of the STAT3 and ERK2 signaling in neurons that express the steroidogenic factor 1 (SF1) in the VMH on energy homeostasis, we used cre-lox technology to generate male and female mice with specific disruption of STAT3 or ERK2 in SF1 neurons of the VMH. We demonstrated that the conditional knockout of STAT3 in SF1 neurons of the VMH did not affect body weight, food intake, energy expenditure and glucose homeostasis in animals on regular chow. However, when challenged with high-fat diet (HFD), loss of STAT3 in SF1 neurons caused a significant increase in body weight, food intake and energy efficiency that was more remarkable in females which also showed a decrease in energy expenditure. In contrast, deletion of ERK2 in SF1 neurons of VMH did not have any impact on energy homeostasis in both regular diet and HFD conditions. In conclusion, STAT3 but not ERK2 signaling in SF1 neurons of VMH plays a crucial role to protect against DIO in a sex-specific pattern.

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Mechanism of Action of Acupuncture in Obesity: A Perspective From the Hypothalamus

Frontiers in Endocrinology ◽

10.3389/fendo.2021.632324 ◽

2021 ◽

Vol 12 ◽

Author(s):

Li Wang ◽

Chao-Chao Yu ◽

Jia Li ◽

Qing Tian ◽

Yan-Jun Du

Keyword(s):

Metabolic Disease ◽

Food Intake ◽

Energy Expenditure ◽

Mechanism Of Action ◽

Energy Homeostasis ◽

Current Evidence ◽

Appetite Regulation ◽

Hypothalamic Nuclei ◽

Treatment Of Obesity ◽

The Relationship

Obesity is a prevalent metabolic disease caused by an imbalance in food intake and energy expenditure. Although acupuncture is widely used in the treatment of obesity in a clinical setting, its mechanism has not been adequately elucidated. As the key pivot of appetite signals, the hypothalamus receives afferent and efferent signals from the brainstem and peripheral tissue, leading to the formation of a complex appetite regulation circuit, thereby effectively regulating food intake and energy homeostasis. This review mainly discusses the relationship between the hypothalamic nuclei, related neuropeptides, brainstem, peripheral signals, and obesity, as well as mechanisms of acupuncture on obesity from the perspective of the hypothalamus, exploring the current evidence and therapeutic targets for mechanism of action of acupuncture in obesity.

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Cold-induced hyperphagia requires AgRP-neuron activation in mice

eLife ◽

10.7554/elife.58764 ◽

2020 ◽

Vol 9 ◽

Author(s):

Jennifer Deem ◽

Chelsea L Faber ◽

Christian Pedersen ◽

Bao Anh Phan ◽

Sarah A Larsen ◽

...

Keyword(s):

Food Intake ◽

Energy Expenditure ◽

Energy Intake ◽

Cold Exposure ◽

Energy Homeostasis ◽

Cold Environment ◽

Energy Demands ◽

Acute Cold Exposure ◽

Neuron Activation ◽

Increase Food Intake

To maintain energy homeostasis during cold exposure, the increased energy demands of thermogenesis must be counterbalanced by increased energy intake. To investigate the neurobiological mechanisms underlying this cold-induced hyperphagia, we asked whether agouti-related peptide (AgRP) neurons are activated when animals are placed in a cold environment and, if so, whether this response is required for the associated hyperphagia. We report that AgRP-neuron activation occurs rapidly upon acute cold exposure, as do increases of both energy expenditure and energy intake, suggesting the mere perception of cold is sufficient to engage each of these responses. We further report that silencing of AgRP neurons selectively blocks the effect of cold exposure to increase food intake but has no effect on energy expenditure. Together, these findings establish a physiologically important role for AgRP neurons in the hyperphagic response to cold exposure.

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Median preoptic area neurons are required for the cooling and febrile activations of brown adipose tissue thermogenesis in rat

Scientific Reports ◽

10.1038/s41598-020-74272-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Ellen Paula Santos da Conceição ◽

Shaun F. Morrison ◽

Georgina Cano ◽

Pierfrancesco Chiavetta ◽

Domenico Tupone

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Cold Exposure ◽

Energy Homeostasis ◽

Preoptic Area ◽

Therapeutic Approaches ◽

Dorsomedial Hypothalamus ◽

Brown Adipose ◽

Brown Adipose Tissue Thermogenesis

Abstract Within the central neural circuitry for thermoregulation, the balance between excitatory and inhibitory inputs to the dorsomedial hypothalamus (DMH) determines the level of activation of brown adipose tissue (BAT) thermogenesis. We employed neuroanatomical and in vivo electrophysiological techniques to identify a source of excitation to thermogenesis-promoting neurons in the DMH that is required for cold defense and fever. Inhibition of median preoptic area (MnPO) neurons blocked the BAT thermogenic responses during both PGE2-induced fever and cold exposure. Disinhibition or direct activation of MnPO neurons induced a BAT thermogenic response in warm rats. Blockade of ionotropic glutamate receptors in the DMH, or brain transection rostral to DMH, blocked cold-evoked or NMDA in MnPO-evoked BAT thermogenesis. RNAscope technique identified a glutamatergic population of MnPO neurons that projects to the DMH and expresses c-Fos following cold exposure. These discoveries relative to the glutamatergic drive to BAT sympathoexcitatory neurons in DMH augment our understanding of the central thermoregulatory circuitry in non-torpid mammals. Our data will contribute to the development of novel therapeutic approaches to induce therapeutic hypothermia for treating drug-resistant fever, and for improving glucose and energy homeostasis.

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