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.

scholarly journals Increasing Energy Flux to Maintain Diet-Induced Weight Loss

Nutrients ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 2533 ◽  
Author(s):  
Christopher L. Melby ◽  
Hunter L. Paris ◽  
R. Drew Sayer ◽  
Christopher Bell ◽  
James O. Hill
Keyword(s):  
Physical Activity ◽  
Weight Loss ◽  
Body Weight ◽  
Energy Balance ◽  
Energy Expenditure ◽  
Energy Flux ◽  
Weight Maintenance ◽  
High Energy ◽  
Daily Energy

Long-term maintenance of weight loss requires sustained energy balance at the reduced body weight. This could be attained by coupling low total daily energy intake (TDEI) with low total daily energy expenditure (TDEE; low energy flux), or by pairing high TDEI with high TDEE (high energy flux). Within an environment characterized by high energy dense food and a lack of need for movement, it may be particularly difficult for weight-reduced individuals to maintain energy balance in a low flux state. Most of these individuals will increase body mass due to an inability to sustain the necessary level of food restriction. This increase in TDEI may lead to the re-establishment of high energy flux at or near the original body weight. We propose that following weight loss, increasing physical activity can effectively re-establish a state of high energy flux without significant weight regain. Although the effect of extremely high levels of physical activity on TDEE may be constrained by compensatory reductions in non-activity energy expenditure, moderate increases following weight loss may elevate energy flux and encourage physiological adaptations favorable to weight loss maintenance, including better appetite regulation. It may be time to recognize that few individuals are able to re-establish energy balance at a lower body weight without permanent increases in physical activity. Accordingly, there is an urgent need for more research to better understand the role of energy flux in long-term weight maintenance.

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 COMPARISON EFFECT OF CV 12, ST 36 AND ST 40 EA ON SHORT TERM ENERGY BALANCE REGULATION IN HIGH FAT DIET RAT

2017 ◽  
Vol 52 (3) ◽  
pp. 174
Author(s):  
Purwo Sri Rejeki ◽  
Harjanto Harjanto ◽  
Raden Argarini ◽  
Imam Subadi
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Energy Balance ◽  
High Fat Diet ◽  
Energy Homeostasis ◽  
Continuous Wave ◽  
Positive Control ◽  
Control Group ◽  
High Fat ◽  
Short Term

The aim of this study was to determine the comparative effects of EA (EA) on the CV12, ST36 and ST40 to weight gain prevention over the short-term regulation of energy balance. The study was conducted with a completely randomized design. Rats were divided into five groups: negative control group (no treatment, n=5), positive control (sham EA/back, n=5), EA CV 12 (n=6), EA ST 36 (n=6) and EA ST 40 (n=7). Rats were exposed to high-fat diet for two weeks and EA was simultaneously performed once daily, five days a week for two weeks with 2 Hz, for 10 minutes with continuous wave. Body weight, BMI, front limb circumference and rear were measured during study. Levels of blood glucose, cholesterol, triglycerides, LDL and HDL were measured at the end of the study; which reflects the short-term regulation of energy homeostasis. For weight loss, EA CV12, ST36 and ST40 group have lost weight significantly compared to the negative and positive control group. The ST40 group has a significant decrease than ST36 and CV12. The most significant decrease in BMI found in the ST40 group. EA did not affect blood glucose levels, but modulated blood lipid profile. In ST 40 group there was a significant decrease in cholesterol, LDL and triglycerides. EA at point ST 40 is potential in preventing increased body weight and BMI in rats exposed to high-fat diet compared to the CV 12 and ST 36. ST 40 is a point with a potential of lowering LDL and triglycerides serum so that it can play a role in the short term regulation of energy homeostasis but also in the prevention of dyslipidemia.

scholarly journals Murine neuronatin deficiency is associated with a hypervariable food intake and bimodal obesity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Irene Cimino ◽  
Debra Rimmington ◽  
Y. C. Loraine Tung ◽  
Katherine Lawler ◽  
Pierre Larraufie ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Energy Expenditure ◽  
Positive Energy ◽  
Chow Diet ◽  
Chromatin Regulator ◽  
Positive Energy Balance ◽  
The Impact ◽  
Deficient Mice

AbstractNeuronatin (Nnat) has previously been reported to be part of a network of imprinted genes downstream of the chromatin regulator Trim28. Disruption of Trim28 or of members of this network, including neuronatin, results in an unusual phenotype of a bimodal body weight. To better characterise this variability, we examined the key contributors to energy balance in Nnat+/−p mice that carry a paternal null allele and do not express Nnat. Consistent with our previous studies, Nnat deficient mice on chow diet displayed a bimodal body weight phenotype with more than 30% of Nnat+/−p mice developing obesity. In response to both a 45% high fat diet and exposure to thermoneutrality (30 °C) Nnat deficient mice maintained the hypervariable body weight phenotype. Within a calorimetry system, food intake in Nnat+/−p mice was hypervariable, with some mice consuming more than twice the intake seen in wild type littermates. A hyperphagic response was also seen in Nnat+/−p mice in a second, non-home cage environment. An expected correlation between body weight and energy expenditure was seen, but corrections for the effects of positive energy balance and body weight greatly diminished the effect of neuronatin deficiency on energy expenditure. Male and female Nnat+/−p mice displayed subtle distinctions in the degree of variance body weight phenotype and food intake and further sexual dimorphism was reflected in different patterns of hypothalamic gene expression in Nnat+/−p mice. Loss of the imprinted gene Nnat is associated with a highly variable food intake, with the impact of this phenotype varying between genetically identical individuals.

Abstract P022: Determinants of Energy Balance: Differences Related to Body Weight and Body Composition

Circulation ◽  
2013 ◽  
Vol 127 (suppl_12) ◽  
Author(s):  
Gregory A Hand ◽  
Robin P Shook ◽  
Jason R Jaggers ◽  
Amanda Paluch ◽  
Vivek K Prasad ◽  
...  
Keyword(s):  
Body Composition ◽  
Body Weight ◽  
Energy Balance ◽  
Energy Expenditure ◽  
Energy Intake ◽  
Positive Association ◽  
Linear Modeling ◽  
Obesity Epidemic ◽  
And Storage ◽  
Lean Group

Conversion, utilization and storage of energy in the regulation of energy balance is poorly understood. These misconceptions arise from confusion related to energy balance and its impact on body weight and composition, and can bias the interpretation of findings that are important for the development of policies addressing the obesity epidemic. PURPOSE: Our purpose was to examine the regulation of interactions between total daily energy intake (TDEI) and energy expenditure (TDEE) in healthy adults. METHODS: Adults not limited by gender, race or ethnicity (n=430; aged 21 to 40; BMI of 20 to 35) participated in a battery of physiological, anthropomorphic, behavioral and psychological measurements that are associated with energy balance regulation. The primary components of energy balance regulation (TDEI and TDEE) were measured by 3 random 24-hour dietary recalls and SenseWear accelerometry, respectively. Body composition was determined by dual x-ray absorptiometry (DXA). Absolute and relative resting metabolic rates (aRMR and rRMR) were determined through hooded indirect calorimetry. General linear modeling was used to examine the relationships of weight and body fatness with TDEI and macronutrient composition as well as the largest components of TDEE including aRMR, rRMR and physical activity energy expenditure (PAEE). In addition, data were compared between participants with a healthy body fat % (below 25; n=123) and obese (at or above 30%; n=241). RESULTS: All results were adjusted for age, gender and race. TDEE was positively associated (r=.47, p<.001) with TDEI. There was a positive association between aRMR (L/min) and weight (r=.743, p<.001). By contrast, rRMR (ml/kg/min) was inversely correlated with body weight (r= -.38; p<.001). TDEI was significantly higher in the lean group (2465±66 to 1878±42, p<.001) with no measureable differences in macronutrient percentages. The lean group had a higher TDEE and PAEE as compared to the obese group. CONCLUSIONS: There was a robust matching of TDEI and TDEE across weight and body composition ranges. Heavy people burned more calories than lighter people although the lighter individuals had a higher rRMR. The leaner group had a higher TDEI, reflecting a potential regulation based on the greater TDEE in this group. Further, the increased TDEE could be explained by the higher PAEE (approximately 500 kcal) in leaner individuals. These findings emphasize that energy expenditure is related to mass rather than body composition. The regulation of energy intake and body composition is multifactorial, with PAEE a significant determinant for energy storage. This study was funded through an unrestricted grant from The Coca-Cola Company.

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 Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats

2008 ◽  
Vol 295 (1) ◽  
pp. E78-E84 ◽  
Author(s):  
Sabine Strassburg ◽  
Stefan D. Anker ◽  
Tamara R. Castaneda ◽  
Lukas Burget ◽  
Diego Perez-Tilve ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Energy Expenditure ◽  
Therapeutic Potential ◽  
Body Weight Gain ◽  
Metabolic Effects ◽  
Positive Energy ◽  
High Dose ◽  
Growth Hormone Secretagogue

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is the only circulating agent to powerfully promote a positive energy balance. Such action is mediated predominantly by central nervous system pathways controlling food intake, energy expenditure, and nutrient partitioning. The ghrelin pathway may therefore offer therapeutic potential for the treatment of catabolic states. However, the potency of the endogenous hormone ghrelin is limited due to a short half-life and the fragility of its bioactivity ensuring acylation at serine 3. Therefore, we tested the metabolic effects of two recently generated GHS-R agonists, BIM-28125 and BIM-28131, compared with ghrelin. All agents were administered continuously for 1 mo in doses of 50 and 500 nmol·kg−1·day−1 using implanted subcutaneous minipumps in rats. High-dose treatment with single agonists or ghrelin increased body weight gain by promoting fat mass, whereas BIM-28131 was the only one also increasing lean mass significantly. Food intake increased during treatment with BIM-28131 or ghrelin, whereas no effects on energy expenditure were detected. With the lower dose, only BIM-28131 had a significant effect on body weight. This also held true when the compound was administered by subcutaneous injection three times/day. No symptoms or signs of undesired effects were observed in any of the studies or treated groups. These results characterize BIM-28131 as a promising GHS-R agonist with an attractive action profile for the treatment of catabolic disease states such as cachexia.

scholarly journals The regulation of body weight: lessons from the seasonal animal

2001 ◽  
Vol 60 (1) ◽  
pp. 127-134 ◽  
Author(s):  
Peter J. Morgan ◽  
Julian G. Mercer
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Energy Homeostasis ◽  
Mutant Mouse ◽  
Neural Pathways ◽  
Control Mechanisms ◽  
Gene Deletions ◽  
Regulate Body Weight ◽  
Human Energy ◽  
Ingestive Behaviour

The hypothalamus is a major regulatory centre involved in the control of many important physiological axes. One of these axes is the regulation of ingestive behaviour. Recent work using a combination of genetic-mutant mouse models together with targeted gene deletions has contributed much to our understanding of how neural pathways of the hypothalamus are involved in the regulation of energy balance in animals. These pathways are also relevant to human energy homeostasis, as mutations in key genes are correlated with obesity. Many of the genes identified mediate the effects of leptin, and are therefore primarily involved in sensing and responding to peripheral signals. In seasonal animals, such as the Siberian hamster (Phodopus sungorus), there is evidence for a higher level of regulation. The systems involved regulate body weight around an apparent 'set-point' through the action of photoperiod via the neurohormone, melatonin. The ability to manipulate energy balance through photoperiod (and melatonin) in the seasonal-animal model offers novel opportunities to identify further fundamental aspects of the control mechanisms involved in the central control of energy homeostasis and body weight.

scholarly journals Energy homeostasis in apolipoprotein AIV and cholecystokinin-deficient mice

2017 ◽  
Vol 313 (5) ◽  
pp. R535-R548 ◽  
Author(s):  
Jonathan Weng ◽  
Danwen Lou ◽  
Stephen C. Benoit ◽  
Natalie Coschigano ◽  
Stephen C. Woods ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Expenditure ◽  
Fat Mass ◽  
High Fat Diet ◽  
Energy Homeostasis ◽  
Lipid Transport ◽  
Fat Absorption ◽  
High Fat ◽  
Reduced Body ◽  
Brown Adipose

Apolipoprotein AIV (ApoAIV) and cholecystokinin (CCK) are well-known satiating signals that are stimulated by fat consumption. Peripheral ApoAIV and CCK interact to prolong satiating signals. In the present study, we hypothesized that ApoAIV and CCK control energy homeostasis in response to high-fat diet feeding. To test this hypothesis, energy homeostasis in ApoAIV and CCK double knockout (ApoAIV/CCK-KO), ApoAIV knockout (ApoAIV-KO), and CCK knockout (CCK-KO) mice were monitored. When animals were maintained on a low-fat diet, ApoAIV/CCK-KO, ApoAIV-KO, and CCK-KO mice had comparable energy intake and expenditure, body weight, fat mass, fat absorption, and plasma parameters relative to the controls. In contrast, these KO mice exhibited impaired lipid transport to epididymal fat pads in response to intraduodenal infusion of dietary lipids. Furthermore, ApoAIV-KO mice had upregulated levels of CCK receptor 2 (CCK2R) in the small intestine while ApoAIV/CCK-KO mice had upregulated levels of CCK2R in the brown adipose tissue. After 20 wk of a high-fat diet, ApoAIV-KO and CCK-KO mice had comparable body weight and fat mass, as well as lower energy expenditure at some time points. However, ApoAIV/CCK-KO mice exhibited reduced body weight and adiposity relative to wild-type mice, despite having normal food intake. Furthermore, ApoAIV/CCK-KO mice displayed normal fat absorption and locomotor activity, as well as enhanced energy expenditure. These observations suggest that mice lacking ApoAIV and CCK have reduced body weight and adiposity, possibly due to impaired lipid transport and elevated energy expenditure.

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