The gut: a key organ coordinating the brain control of energy homeostasis

AbstractThyroid hormone (TH) regulation is important for development, energy homeostasis, heart function, and bone formation. To control the effects of TH in target organs, the hypothalamus-pituitary-thyroid (HPT) axis and the tissue-specific availability of TH are highly regulated by negative feedback. To exert a central feedback, TH must enter the brain via specific transport mechanisms and cross the blood-brain barrier. Here, tanycytes, which are located in the ventral walls of the 3rd ventricle in the mediobasal hypothalamus (MBH), function as gatekeepers. Tanycytes are able to transport, sense, and modify the release of hormones of the HPT axis and are involved in feedback regulation. In this review, we focus on the relevance of tanycytes in thyrotropin-releasing hormone (TRH) release and review available genetic tools to investigate the physiological functions of these cells.

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Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions

Acta Endocrinologica ◽

10.1530/eje.0.1490079 ◽

2003 ◽

Vol 149 (2) ◽

pp. 79-90 ◽

Cited By ~ 160

Author(s):

ML Raffin-Sanson ◽

Y de Keyzer ◽

X Bertagna

Keyword(s):

Anterior Pituitary ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Single Gene ◽

Local Production ◽

Biological Functions ◽

Multiple Functions ◽

Pathological Conditions ◽

Recent Developments ◽

The Brain

Proopiomelanocortin (POMC) is the polypeptide precursor of ACTH. First discovered in anterior pituitary corticotroph cells, it has more recently been revealed to have many other physiological aspects. The fine molecular mechanisms of ACTH biosynthesis show that ACTH is but one piece of a puzzle which contains many other peptides. Present in various tIssues, among which are pituitary, hypothalamus, central nervous system and skin, POMC undergoes extensive post-translational processing. This processing is tIssue-specific and generates, depending on the case, various sets of peptides involved in completely diverse biological functions. POMC expressed in corticotroph cells of the pituitary is necessary for adrenal function. Recent developments have shown that POMC-expressing neurons in the brain play a major role in the control of pain and energy homeostasis. Local production of POMC-derived peptides in skin may influence melanogenesis. A still unknown function in the placenta is likely.POMC has become a paradigmatic polypeptide precursor model illustrating the variable roles of a single gene and its various products in different localities.

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Contribution of Neuroinflammation to the Pathogenesis of Cancer Cachexia

Mediators of Inflammation ◽

10.1155/2015/801685 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 11

Author(s):

Alessio Molfino ◽

Gianfranco Gioia ◽

Filippo Rossi Fanelli ◽

Alessandro Laviano

Keyword(s):

Adipose Tissue ◽

Food Intake ◽

Proinflammatory Cytokines ◽

Adaptive Response ◽

Energy Homeostasis ◽

Cancer Cachexia ◽

Behavioral Changes ◽

Brain Areas ◽

Functional Changes ◽

The Brain

Inflammation characterizes the course of acute and chronic diseases and is largely responsible for the metabolic and behavioral changes occurring during the clinical journey of patients. Robust data indicate that, during cancer, functional modifications within brain areas regulating energy homeostasis contribute to the onset of anorexia, reduced food intake, and increased catabolism of muscle mass and adipose tissue. In particular, functional changes are associated with increased hypothalamic concentration of proinflammatory cytokines, which suggests that neuroinflammation may represent the adaptive response of the brain to peripheral challenges, including tumor growth. Within this conceptual framework, the vagus nerve appears to be involved in conveying alert signals to the hypothalamus, whereas hypothalamic serotonin appears to contribute to triggering catabolic signals.

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GEOFFREY HARRIS PRIZE LECTURE 2018: Novel pathways regulating neuroendocrine function, energy homeostasis and metabolism in humans

Acta Endocrinologica ◽

10.1530/eje-18-0847 ◽

2019 ◽

Vol 180 (2) ◽

pp. R59-R71 ◽

Cited By ~ 6

Author(s):

Aimilia Eirini Papathanasiou ◽

Eric Nolen-Doerr ◽

Olivia M Farr ◽

Christos S Mantzoros

Keyword(s):

Energy Homeostasis ◽

Endocrine System ◽

Current Evidence ◽

Energy Reserves ◽

Neuroendocrine Function ◽

Available Energy ◽

Neuroendocrine Response ◽

Leptin Deficiency ◽

Molecular Signals ◽

The Brain

The discovery of leptin, an adipocyte-secreted hormone, set the stage for unraveling the mechanisms dictating energy homeostasis, revealing adipose tissue as an endocrine system that regulates appetite and body weight. Fluctuating leptin levels provide molecular signals to the brain regarding available energy reserves modulating energy homeostasis and neuroendocrine response in states of leptin deficiency and to a lesser extent in hyperleptinemic states. While leptin replacement therapy fails to provide substantial benefit in common obesity, it is an effective treatment for congenital leptin deficiency and states of acquired leptin deficiency such as lipodystrophy. Current evidence suggests that regulation of eating behavior in humans is not limited to homeostatic mechanisms and that the reward, attention, memory and emotion systems are involved, participating in a complex central nervous system network. It is critical to study these systems for the treatment of typical obesity. Although progress has been made, further studies are required to unravel the physiology, pathophysiology and neurobehavioral mechanisms underlying potential treatments for weight-related problems in humans.

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The effects of the form of sugar (solid vs. beverage) on body weight and fMRI activation: A randomized controlled pilot study

PLoS ONE ◽

10.1371/journal.pone.0251700 ◽

2021 ◽

Vol 16 (5) ◽

pp. e0251700

Author(s):

John W. Apolzan ◽

Owen T. Carmichael ◽

Krystal M. Kirby ◽

Sreekrishna R. Ramakrishnapillai ◽

Robbie A. Beyl ◽

...

Keyword(s):

Body Weight ◽

Energy Homeostasis ◽

Pilot Trial ◽

Brain Regions ◽

Reward Processing ◽

Daily Consumption ◽

Fed State ◽

Randomized Controlled ◽

The Right ◽

The Brain

Objective To test if sugar sweetened beverages (SSBs) and sugar sweetened solids (SSSs) have differential effects on body weight and reward processing in the brain. Methods In a single blind randomized controlled pilot trial (RCT), twenty participants with BMI between 20 and 40 kg/m2 were randomized to consume a 20 fluid ounce soda (SSB, 248 kcal) or the equivalent in solid form (SSS; similar to thick gelatin or gummy candy) daily. At baseline and day 28, fasting body weight and fed-state BOLD fMRI of the brain were assessed. Differences in fMRI signals between views of low-fat (LF (<30%)) high sugar (HS (>30%)) food, and non-food images were calculated in brain regions implicated in energy homeostasis, taste, and reward. Results All participants in the SSB (6F 4M; 8 Caucasian; 36±14 y, 28.2±5.5 kg/m2; Mean±SD) and SSS (3F 7M; 6 Caucasian; 39±12; 26.3±4.4) groups completed the study. Weight change was 0.27±0.78 kg between SSB and SSS participants. Changes in the fMRI response to LF/HS foods in reward, homeostatic and taste regions tended to not be different between the groups over the four weeks. However, activation of the right substantia nigra increased following the SSB but decreased activation following the SSS in response to LF/HS foods over 28 days (-0.32±0.12). Ratings of wanting for LF/HS foods were correlated with activation in several brain regions, including the OFC. Conclusions Change in weight was modest between the groups in this study. Daily consumption of a SSB over 28 days led to mixed responses to LF/HS foods in areas of the brain associated with reward. Ratings of wanting are correlated with fMRI activation inside an MRI scanner.

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The Gut Microbiome, Obesity, and Weight Control in Women’s Reproductive Health

Western Journal of Nursing Research ◽

10.1177/0193945917697223 ◽

2017 ◽

Vol 39 (8) ◽

pp. 1094-1119 ◽

Cited By ~ 7

Author(s):

K. Leigh Greathouse ◽

Mary Ann Faucher ◽

Marie Hastings-Tolsma

Keyword(s):

Reproductive Health ◽

Gut Microbiome ◽

Weight Control ◽

Energy Homeostasis ◽

Energy Extraction ◽

Human Gut ◽

Microbiome Research ◽

Prevalence Of Obesity ◽

Offspring Health ◽

The Brain

The microbes residing in the human gut, referred to as the microbiome, are intricately linked to energy homeostasis and subsequently obesity. Integral to the origins of obesity, the microbiome is believed to affect not only health of the human gut but also overall health. This microbiome–obesity association is mediated through the process of energy extraction, metabolism, and cross talk between the brain and the gut microbiome. Host exposures, including diet, that potentially modify genetic predisposition to obesity and affect weight management are reviewed. The higher prevalence of obesity among women and recent evidence linking obesity during pregnancy with offspring health make this topic particularly relevant. Current limitations in microbiome research to address obesity and future advances in this field are described. Applications of this science with respect to applied nursing and overall health care in general are included, with emphasis on the reproductive health of women and their offspring.

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Influence of a nonforage diet on plasma leptin in dairy goats throughout lactation

Proceedings of the British Society of Animal Science ◽

10.1017/s1752756200007535 ◽

2002 ◽

Vol 2002 ◽

pp. 97-97

Author(s):

F. Rosi ◽

L. Rapetti

Keyword(s):

Energy Homeostasis ◽

Peptide Hormone ◽

Dairy Goats ◽

Lactating Goats ◽

Energy Stores ◽

The Status ◽

Plasma Leptin ◽

Body Energy ◽

The Brain ◽

By Products

Leptin is a 16kDa peptide hormone mainly secreted by fat cells to regulate of food intake and energy homeostasis, and to signal the status of body energy stores to the brain (Houseknecht et al., 1998). In ruminant, reducing feedstuffs particle size increases DM intake, particularly if feedstuffs quality is poor, due to a shorter retention time of the particles in the rumen. By-products are included in the ration to supply energy and protein, but they have often a high content of fibre. The by-product fibre has different properties than forage NDF, being characterised by particles of small dimensions and a high density. The aim of this study was to compare the plasma level of leptin in lactating goats fed a traditional silage-based diet or a totally free forage diet, throughout lactation and during the pre and post-feeding state.

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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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Neural Underpinnings of Obesity: The Role of Oxidative Stress and Inflammation in the Brain

Antioxidants ◽

10.3390/antiox9101018 ◽

2020 ◽

Vol 9 (10) ◽

pp. 1018

Author(s):

Caitlyn A. Mullins ◽

Ritchel B. Gannaban ◽

Md Shahjalal Khan ◽

Harsh Shah ◽

Md Abu B. Siddik ◽

...

Keyword(s):

Oxidative Stress ◽

Energy Homeostasis ◽

Dorsal Striatum ◽

Brain Regions ◽

Therapeutic Interventions ◽

Low Grade ◽

Obesity Prevalence ◽

Beneficial Effects ◽

The Brain

Obesity prevalence is increasing at an unprecedented rate throughout the world, and is a strong risk factor for metabolic, cardiovascular, and neurological/neurodegenerative disorders. While low-grade systemic inflammation triggered primarily by adipose tissue dysfunction is closely linked to obesity, inflammation is also observed in the brain or the central nervous system (CNS). Considering that the hypothalamus, a classical homeostatic center, and other higher cortical areas (e.g. prefrontal cortex, dorsal striatum, hippocampus, etc.) also actively participate in regulating energy homeostasis by engaging in inhibitory control, reward calculation, and memory retrieval, understanding the role of CNS oxidative stress and inflammation in obesity and their underlying mechanisms would greatly help develop novel therapeutic interventions to correct obesity and related comorbidities. Here we review accumulating evidence for the association between ER stress and mitochondrial dysfunction, the main culprits responsible for oxidative stress and inflammation in various brain regions, and energy imbalance that leads to the development of obesity. Potential beneficial effects of natural antioxidant and anti-inflammatory compounds on CNS health and obesity are also discussed.

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LGR4 and Its Ligands, R-Spondin 1 and R-Spondin 3, Regulate Food Intake in the Hypothalamus of Male Rats

Endocrinology ◽

10.1210/en.2013-1550 ◽

2014 ◽

Vol 155 (2) ◽

pp. 429-440 ◽

Cited By ~ 11

Author(s):

Ji-Yao Li ◽

Biaoxin Chai ◽

Weizhen Zhang ◽

Danielle M. Fritze ◽

Chao Zhang ◽

...

Keyword(s):

In Situ Hybridization ◽

Food Intake ◽

Neuropeptide Y ◽

Paraventricular Nucleus ◽

Median Eminence ◽

Energy Homeostasis ◽

Male Rats ◽

The Third ◽

The Brain

The hypothalamus plays a key role in the regulation of feeding behavior. Several hypothalamic nuclei, including the arcuate nucleus (ARC), paraventricular nucleus, and ventromedial nucleus of the hypothalamus (VMH), are involved in energy homeostasis. Analysis of microarray data derived from ARC revealed that leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) is highly expressed. LGR4, LGR5, and LGR6 form a subfamily of closely related receptors. Recently, R-spondin (Rspo) family proteins were identified as ligands of the LGR4 subfamily. In the present study, we investigated the distribution and function of LGR4–LGR6 and Rspos (1–4) in the brain of male rat. In situ hybridization showed that LGR4 is expressed in the ARC, VMH, and median eminence of the hypothalamus. LGR4 colocalizes with neuropeptide Y, proopiomelanocortin, and brain-derived neurotrophic factor neurons. LGR5 is not detectable with in situ hybridization; LGR6 is only expressed in the epithelial lining of the lower portion of the third ventricle and median eminence. Rspo1 is expressed in the VMH and down-regulated with fasting. Rspo3 is expressed in the paraventricular nucleus and also down-regulated with fasting. Rspos 1 and 3 colocalize with the neuronal marker HuD, indicating that they are expressed by neurons. Injection of Rspo1 or Rspo3 into the third brain ventricle inhibited food intake. Rspo1 decreased neuropeptide Y and increased proopiomelanocortin expression in the ARC. Rspo1 and Rspo3 mRNA is up-regulated by insulin. These data indicate that Rspo1 and Rspo3 and their receptor LGR4 form novel circuits in the brain to regulate energy homeostasis.

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