scholarly journals Lateral Hypothalamic Mc3R-Expressing Neurons Modulate Locomotor Activity, Energy Expenditure, and Adiposity in Male Mice

Endocrinology ◽  
2018 ◽  
Vol 160 (2) ◽  
pp. 343-358 ◽  
Author(s):  
Hongjuan Pei ◽  
Christa M Patterson ◽  
Amy K Sutton ◽  
Korri H Burnett ◽  
Martin G Myers ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Energy Balance ◽  
Energy Expenditure ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Balance Control ◽  
Melanocortin System ◽  
Brain Areas ◽  
Hypothalamic Area ◽  
Lateral Hypothalamic

Abstract The central melanocortin system plays a crucial role in the control of energy balance. Although the decreased energy expenditure and increased adiposity of melanocortin-3 receptor (Mc3R)–null mice suggest the importance of Mc3R-regulated neurons in energy homeostasis, the roles for specific subsets of Mc3R neurons in energy balance have yet to be determined. Because the lateral hypothalamic area (LHA) contributes to the control of energy expenditure and feeding, we generated Mc3rcre mice to determine the roles of LHA Mc3R (Mc3RLHA) neurons in energy homeostasis. We found that Mc3RLHA neurons overlap extensively with LHA neuron markers that contribute to the control of energy balance (neurotensin, galanin, and leptin receptor) and project to brain areas involved in the control of feeding, locomotion, and energy expenditure, consistent with potential roles for Mc3RLHA neurons in these processes. Indeed, selective chemogenetic activation of Mc3RLHA neurons increased locomotor activity and augmented refeeding after a fast. Although the ablation of Mc3RLHA neurons did not alter food intake, mice lacking Mc3RLHA neurons displayed decreased energy expenditure and locomotor activity, along with increased body mass and adiposity. Thus, Mc3R neurons lie within LHA neurocircuitry that modulates locomotor activity and energy expenditure and contribute to energy balance control.

scholarly journals Lateral Hypothalamic Area Neurotensin Neurons Are Required for Control of Orexin Neurons and Energy Balance

Endocrinology ◽  
2018 ◽  
Vol 159 (9) ◽  
pp. 3158-3176 ◽  
Author(s):  
Juliette Brown ◽  
Andrew Sagante ◽  
Thomas Mayer ◽  
Anna Wright ◽  
Raluca Bugescu ◽  
...  
Keyword(s):  
Body Weight ◽  
Locomotor Activity ◽  
Energy Balance ◽  
Large Population ◽  
Lateral Hypothalamic Area ◽  
Hypothalamic Area ◽  
Genetic Ablation ◽  
Lateral Hypothalamic ◽  
Adult Mice ◽  
Locomotor Behaviors

Abstract The lateral hypothalamic area (LHA) is essential for motivated ingestive and locomotor behaviors that impact body weight, yet it remains unclear how the neurochemically defined subpopulations of LHA neurons contribute to energy balance. In particular, the role of the large population of LHA neurotensin (Nts) neurons has remained ambiguous due to the lack of methods to easily visualize and modulate these neurons. Because LHA Nts neurons are activated by leptin and other anorectic cues and they modulate dopamine or local LHA orexin neurons implicated in energy balance, they may have important, unappreciated roles for coordinating behaviors necessary for proper body weight. In this study, we genetically ablated or chemogenetically inhibited LHA Nts neurons in adult mice to determine their necessity for control of motivated behaviors and body weight. Genetic ablation of LHA Nts neurons resulted in profoundly increased adiposity compared with mice with intact LHA Nts neurons, as well as diminished locomotor activity, energy expenditure, and water intake. Complete loss of LHA Nts neurons also led to downregulation of orexin, revealing important cross-talk between the LHA Nts and orexin populations in maintenance of behavior and body weight. In contrast, chemogenetic inhibition of intact LHA Nts neurons did not disrupt orexin expression, but it suppressed locomotor activity and the adaptive response to leptin. Taken together, these data reveal the necessity of LHA Nts neurons and their activation for controlling energy balance, and that LHA Nts neurons influence behavior and body weight via orexin-dependent and orexin-independent mechanisms.

Paraventricular Calcitonin Receptor Expressing Neurons Modulate Energy Homeostasis in Male Mice

Endocrinology ◽  
2021 ◽  
Author(s):  
Ian E Gonzalez ◽  
Julliana Ramirez-Matias ◽  
Chunxia Lu ◽  
Warren Pan ◽  
Allen Zhu ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Energy Expenditure ◽  
Energy Homeostasis ◽  
Balance Control ◽  
Weight Maintenance ◽  
Abnormal Development ◽  
Calcitonin Receptor ◽  
Neuronal Populations ◽  
Treatment And Prevention

Abstract The paraventricular nucleus of the hypothalamus (PVH) is a heterogeneous collection of neurons that play important roles in modulating feeding and energy expenditure. Abnormal development or ablation of the PVH results in hyperphagic obesity and defects in energy expenditure whereas selective activation of defined PVH neuronal populations can suppress feeding and may promote energy expenditure. Here, we characterize the contribution of calcitonin receptor-expressing PVH neurons (CalcR PVH) to energy balance control. We used Cre-dependent viral tools delivered stereotaxically to the PVH of CalcR 2Acre mice to activate, silence and trace CalcR PVH neurons and determine their contribution to body weight regulation. Immunohistochemistry of fluorescently-labelled CalcR PVH neurons demonstrates that CalcR PVH neurons are largely distinct from several PVH neuronal populations involved in energy homeostasis; these neurons project to regions of the hindbrain that are implicated in energy balance control, including the nucleus of the solitary tract and the parabrachial nucleus. Acute activation of CalcR PVH neurons suppresses feeding without appreciably augmenting energy expenditure, whereas their silencing leads to obesity that may be due in part due to loss of PVH melanocortin-4 receptor (MC4R) signaling. These data show that CalcR PVH neurons are an essential component of energy balance neurocircuitry and their function is important for body weight maintenance. A thorough understanding of the mechanisms by which CalcR PVH neurons modulate energy balance might identify novel therapeutic targets for the treatment and prevention of obesity.

scholarly journals OR04-03 Calcitonin Receptor Expressing Neurons in the PVH Regulate Feeding Behavior

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Ian Enrique Gonzalez ◽  
Wenwen Cheng ◽  
Warren Pan ◽  
Chunxia Lu ◽  
Julliana Ramirez-Matias ◽  
...  
Keyword(s):  
Energy Balance ◽  
Food Intake ◽  
Energy Expenditure ◽  
Feeding Behavior ◽  
Tetanus Toxin ◽  
Energy Homeostasis ◽  
Balance Control ◽  
Brain Regions ◽  
Calcitonin Receptor ◽  
Cumulative Food Intake

Abstract The paraventricular nucleus of the hypothalamus (PVH) is a brain region crucial for energy homeostasis. Abnormal PVH development or damage leads to hyperphagic obesity and energy expenditure deficits underscoring the importance of PVH neuronal activity in energy balance control. Application of salmon calcitonin (sCT) to the PVH suppresses feeding and calcitonin receptor (CalcR) is highly expressed in the PVH of rodents suggesting that CalcR-expressing PVH neurons contribute to energy homeostasis. In situ hybridization reveals that many CalcRPVH neurons express melanocortin-4 receptor (MC4R), a receptor required for normal feeding behavior. To investigate the physiologic roles of CalcRPVH neurons, we generated CalcR-2a-Cre knock-in mice to manipulate CalcR-expressing cells. Deletion of MC4R from CalcR expressing cells using Cre-loxP technology resulted in profound obesity in both male and female mice by 16 weeks of age. This weight gain was attributable to hyperphagia, as cumulative food intake of the MC4R deleted mice was significantly greater than the controls and energy expenditure measurements acquired through CLAMS analysis were not significantly different. To determine the brain regions engaged by CalcRPVH neurons, we used anterograde Cre-dependent viral tracing reagents injected into the PVH of CalcR-Cre mice, and found that CalcRPVH neurons project to brain regions implicated in energy balance control, including the nucleus of the solitary tract and the parabrachial nucleus. To assess the acute effects of activating CalcRPVH neurons, we used DREADD technology to chemogenetically activate CalcRPVH neurons. CalcRPVH neuron activation suppressed feeding but had no significant effect on energy expenditure. To determine if the activity of CalcRPVH neurons is required for energy homeostasis, we silenced them using Cre-dependent tetanus toxin virus. Male mice with tetanus toxin silenced CalcRPVH neurons were obese 7 weeks following injection in part due to greater cumulative food intake; CLAMS analysis revealed no differences in energy expenditure. Mice with silenced CalcRPVH neurons as well as mice with CalcR deleted from the PVH had normal anorectic responses to sCT, suggesting sCT-induced anorexia does not require CalcRPVH neurons or CalcR expression in the PVH. Taken together, these findings suggest CalcRPVH neurons are an essential component of feeding and energy homeostatic circuitry.

Mice with MCH ablation resist diet-induced obesity through strain-specific mechanisms

2005 ◽  
Vol 289 (1) ◽  
pp. R117-R124 ◽  
Author(s):  
Efi Kokkotou ◽  
Justin Y. Jeon ◽  
Xiaomei Wang ◽  
Francis E. Marino ◽  
Michael Carlson ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Energy Balance ◽  
Energy Expenditure ◽  
Energy Homeostasis ◽  
Relative Increase ◽  
Potential Interaction ◽  
Mouse Strains ◽  
Genetic Ablation ◽  
Melanin Concentrating Hormone ◽  
Different Strains

Genetics and environment contribute to the development of obesity, in both humans and rodents. However, the potential interaction between genes important in energy balance, strain background, and dietary environment has been only minimally explored. We investigated the effects of genetic ablation of melanin-concentrating hormone (MCH), a neuropeptide with a key role in energy balance, with chow and a high-fat diet (HFD) in two different mouse strains, one obesity-prone (C57BL/6) and the other obesity-resistant (129). Substantial differences were seen in wild-type (WT) animals of different strains. 129 animals had significantly lower levels of spontaneous locomotor activity than C57BL/6; however, 129 mice gained less weight on both chow and HFD. In both strains, deletion of MCH led to attenuated weight gain compared with WT counterparts, an effect secondary to increased energy expenditure. In both strains, feeding a HFD led to further increases in energy expenditure in both WT and MCH-KO mice; however, this increase was more pronounced in 129 mice. In addition, mice lacking MCH have a phenotype of increased locomotor activity, an effect also seen in both strains. The relative increase in activity in MCH−/− mice is modest in animals fed chow but increases substantially when animals are placed on HFD. These studies reinforce the important role of MCH in energy homeostasis and indicate that MCH is a plausible target for antiobesity therapy.

Glycogenic induction of thyroid hormone conversion and leptin system activation in the liver of postpartum dairy cows

2009 ◽  
Vol 57 (1) ◽  
pp. 139-146
Author(s):  
Andrea Győrffy ◽  
Mónika Keresztes ◽  
Vera Faigl ◽  
Vilmos Frenyó ◽  
Margit Kulcsár ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Energy Balance ◽  
Dairy Cows ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Energy Content ◽  
Short Form ◽  
Negative Energy ◽  
Type I ◽  
Leptin System

In the regulation of energy metabolism, the liver plays an important role in the reinforcement of energy production. In periparturient cows the energy homeostasis turns into a negative energy balance that may shift the physiological regulation of energy balance towards pathological processes. Propylene glycol (PG), as a complementary source of energy used in the nutrition of dairy cows, alters systemic thyroid hormone economy; however, the exact mechanism through which highly glycogenic feed supplements impact liver metabolism is little known. Previous studies showed that only leptin receptors are expressed in the liver of cows, and now we report that leptin mRNA is expressed in the liver of cows as well. The present results show that the mRNA of leptin and its receptors are differentially modulated by the increased energy content of the feed consumed. Simultaneous changes in hepatic type I deiodinase activity suggest that hepatic modulation of the leptin system by PG supplementation may be mediated by an increased local thyroxine-triiodothyronine conversion. Since PG supplementation with simultaneous T4–T3 turnover and increased hepatic leptin- and short-form leptin receptor mRNA were not associated with a significant change in hepatic total lipid levels, it is suggested that the leptin system, directly or indirectly modulated by thyroid hormones, may represent a local defence mechanism to prevent fatty liver formation.

Energy balance of rats with lateral hypothalamic lesions

1982 ◽  
Vol 242 (4) ◽  
pp. E273-E279 ◽  
Author(s):  
S. W. Corbett ◽  
R. E. Keesey
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Energy Expenditure ◽  
Caloric Intake ◽  
Energy Utilization ◽  
Lateral Hypothalamic ◽  
Energy Needs ◽  
Body Weights ◽  
Maintain Body Weight

Rats with lateral hypothalamic (LH) lesions maintain body weight at a chronically reduced percentage of nonlesioned controls. An assessment of how they achieve energy balance at subnormal weight levels entailed a determination of both their energy intake and their energy expended or lost in processing ingested food, on basal heat production, on activity, and in feces or urine. It was found that the caloric intake and expenditure of LH-lesioned animals, though significantly lower than those of controls, were appropriate to the reduced metabolic body size (BW0.75) that they maintained. Likewise, energy expenditure in the LH-lesioned animals was normal in that the proportion of their ingested energy relegated to 1) basal metabolism, 2) the processing food, and 3) activity was the same as that of nonlesioned controls. Thus, unlike nonlesioned rats, which at lowered body weights both decrease their energy needs and reorder the pattern of energy expenditure, LH-lesioned animals display a normal pattern of energy utilization at reduced weight levels. These findings provide further evidence that lateral hypothalamic mechanisms play an important role in setting the level at which body weight is regulated.

scholarly journals Characterization of Leptin-Responsive Neurons in the Caudal Brainstem

Endocrinology ◽  
2006 ◽  
Vol 147 (7) ◽  
pp. 3190-3195 ◽  
Author(s):  
Kate L. J. Ellacott ◽  
Ilia G. Halatchev ◽  
Roger D. Cone
Keyword(s):  
Green Fluorescent Protein ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Fluorescent Protein ◽  
Physiological Role ◽  
Cell Group ◽  
Melanocortin System ◽  
Peptide Precursor ◽  
Green Fluorescent

The central melanocortin system plays a key role in the regulation of energy homeostasis. Neurons containing the peptide precursor proopiomelanocortin (POMC) are found at two sites in the brain, the arcuate nucleus of the hypothalamus (ARC) and the caudal region of the nucleus of the solitary tract (NTS). ARC POMC neurons, which also express cocaine- and amphetamine-regulated transcript (CART), are known to mediate part of the response to factors regulating energy homeostasis, such as leptin and ghrelin. In contrast, the physiological role(s) of the POMC neurons in the caudal brainstem are not well characterized. However, development of a transgenic mouse expressing green fluorescent protein under the control of the POMC promoter [POMC-enhanced green fluorescent protein (EGFP) mouse] has aided the study of these neurons. Indeed, recent studies have shown significant activation of NTS POMC-EGFP cells by the gut released satiety factor cholecystokinin (CCK). Here we show that peripheral leptin administration induces the expression of phospho-signal transducer and activator of transcription 3 immunoreactivity (pSTAT3-IR), a marker of leptin receptor signaling, in more than 50% of NTS POMC-EGFP neurons. Furthermore, these POMC-EGFP neurons comprise 30% of all pSTAT3-IR cells in the NTS. Additionally, we also show that in contrast to the ARC population, NTS POMC-EGFP neurons do not coexpress CART immunoreactivity. These data suggest that NTS POMC neurons may participate with ARC POMC cells in mediating some of the effects of leptin and thus comprise a novel cell group regulated by both long-term adipostatic signals and satiety factors such as CCK.

scholarly journals Preoptic leptin signaling modulates energy balance independent of body temperature regulation

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Sangho Yu ◽  
Helia Cheng ◽  
Marie François ◽  
Emily Qualls-Creekmore ◽  
Clara Huesing ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Body Temperature ◽  
Energy Expenditure ◽  
Ambient Temperature ◽  
Temperature Regulation ◽  
Leptin Receptor ◽  
Energy State ◽  
Body Temperature Regulation ◽  
Leptin Signaling

The adipokine leptin acts on the brain to regulate energy balance but specific functions in many brain areas remain poorly understood. Among these, the preoptic area (POA) is well known to regulate core body temperature by controlling brown fat thermogenesis, and we have previously shown that glutamatergic, long-form leptin receptor (Lepr)-expressing neurons in the POA are stimulated by warm ambient temperature and suppress energy expenditure and food intake. Here we further investigate the role of POA leptin signaling in body weight regulation and its relationship to body temperature regulation in mice. We show that POA Lepr signaling modulates energy expenditure in response to internal energy state, and thus contributes to body weight homeostasis. However, POA leptin signaling is not involved in ambient temperature-dependent metabolic adaptations. Our study reveals a novel cell population through which leptin regulates body weight.

scholarly journals Obesity remodels activity and transcriptional state of a lateral hypothalamic brake on feeding

Science ◽  
2019 ◽  
Vol 364 (6447) ◽  
pp. 1271-1274 ◽  
Author(s):  
Mark A. Rossi ◽  
Marcus L. Basiri ◽  
Jenna A. McHenry ◽  
Oksana Kosyk ◽  
James M. Otis ◽  
...  
Keyword(s):  
Energy Homeostasis ◽  
Health Concern ◽  
Hypothalamic Area ◽  
Obesity Epidemic ◽  
Glutamatergic Neurons ◽  
Two Photon ◽  
Lateral Hypothalamic ◽  
The Brain ◽  
Transcriptional State

The current obesity epidemic is a major worldwide health concern. Despite the consensus that the brain regulates energy homeostasis, the neural adaptations governing obesity are unknown. Using a combination of high-throughput single-cell RNA sequencing and longitudinal in vivo two-photon calcium imaging, we surveyed functional alterations of the lateral hypothalamic area (LHA)—a highly conserved brain region that orchestrates feeding—in a mouse model of obesity. The transcriptional profile of LHA glutamatergic neurons was affected by obesity, exhibiting changes indicative of altered neuronal activity. Encoding properties of individual LHA glutamatergic neurons were then tracked throughout obesity, revealing greatly attenuated reward responses. These data demonstrate how diet disrupts the function of an endogenous feeding suppression system to promote overeating and obesity.

scholarly journals Signaling through Tyr985 of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance

2009 ◽  
Vol 30 (7) ◽  
pp. 1650-1659 ◽  
Author(s):  
Jia You ◽  
Yue Yu ◽  
Lei Jiang ◽  
Wenxia Li ◽  
Xinxin Yu ◽  
...  
Keyword(s):  
Energy Balance ◽  
Energy Homeostasis ◽  
Leptin Receptor ◽  
Negative Regulator ◽  
Leptin Resistance ◽  
Leptin Signaling ◽  
Diet Induced Obesity ◽  
Long Form ◽  
Elevated Expression ◽  
Multiple Signaling

ABSTRACT Leptin regulates energy homeostasis through central activation of multiple signaling pathways mediated by Ob-Rb, the long form of leptin receptor. Leptin resistance underlies the pathogenic development of obesity, which is closely associated with environmental factors. To further understand the physiological function of leptin signaling mechanisms, we generated a knock-in line of mice (Y985F) expressing a mutant Ob-Rb with a phenylalanine substitution for Tyr985, one of the three intracellular tyrosines that mediate leptin's signaling actions. Surprisingly, whereas young homozygous Y985F animals were slightly leaner, they exhibit adult-onset or diet-induced obesity. Importantly, both age-dependent and diet-induced deterioration of energy balance was paralleled with pronounced leptin resistance, which was largely attributable to attenuation of leptin-responsive hypothalamic STAT3 activation as well as prominently elevated expression of hypothalamic SOCS3, a key negative regulator of leptin signaling. Thus, these results unmask distinct binary roles for Try985-mediated signaling in energy metabolism, acting as an age/diet-dependent regulatory switch to counteract age-associated or diet-induced obesity.

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