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Hypothalamic Regulation of Obesity

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 59669

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Dr. Rosalía Rodríguez-Rodríguez

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Guest Editor

Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, E-08195 Sant Cugat del Vallès, Spain
Interests: obesity; hypothalamus; metabolic syndrome; vascular function; endocannabinoids
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Dr. Cristina Miralpeix

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Guest Editor

INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, Bordeaux, France
Interests: obesity; hypothalamic neurons; CB1R
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The obesity epidemic represents a major socioeconomic problem that urgently requires a better understanding of the mechanisms mediating the imbalance between food intake and energy expenditure and of obesity-related metabolic and cardiovascular complications. Gaining insight into the cellular basis of obesity could lay the foundations for the development of new therapeutic strategies.

In the last few decades, it has been strongly demonstrated that the hypothalamus is the critical brain region regulating energy homeostasis. The hypothalamus contains hormonal- and nutrient-sensing nuclei that organize central and peripheral responses for maintaining normal body weight, food intake, energy expenditure and nutrient partitioning. Within the hypothalamus, numerous specialized neuronal populations are connected to each other and also to various extrahypothalamic brain regions to coordinate energy homeostasis. Evidence also suggests the participation of non-neuronal populations, such as astrocytes, or even the interesting interplay between astrocytes and hypothalamic neurons, whose disruption leads to insulin resistance and obesity.

This Special Issue will report on the most recent insights into the hypothalamic neuronal and non-neuronal pathways involved in obesity development. Novel findings related to key systems, such as endocannabinoid and melanocortin-related pathways, in the hypothalamus will be discussed. In addition, the emerging contribution of the cross-talk between the hypothalamus and peripheral tissues, such as gut and adipose tissue, in obesity will be a promising topic to deal with. Therefore, here we will present an overview of the most recent mechanisms underlying the hypothalamic regulation of obesity and the impact of these investigations in the prevention and treatment of human obesity.

Dr. Rosalía Rodríguez-Rodríguez
Guest Editor

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Keywords

obesity
food intake
energy expenditure
hypothalamus
energy homeostasis
neurons
astrocytes
insulin resistance
glucose homeostasis
lipid metabolism
adipose tissue
gut-brain axis

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Published Papers (12 papers)

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Editorial

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4 pages, 592 KiB

Open AccessEditorial

Hypothalamic Regulation of Obesity

by Rosalía Rodríguez-Rodríguez and Cristina Miralpeix

Int. J. Mol. Sci. 2021, 22(24), 13459; https://doi.org/10.3390/ijms222413459 - 15 Dec 2021

Cited by 6 | Viewed by 3034

Abstract

Obesity has now reached pandemic proportions and represents a major socioeconomic and health problem in our societies [...] Full article

(This article belongs to the Special Issue Hypothalamic Regulation of Obesity)

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Research

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35 pages, 23841 KiB

Open AccessArticle

A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer’s Disease, the 5XFAD Mouse

by Antonio J. López-Gambero, Cristina Rosell-Valle, Dina Medina-Vera, Juan Antonio Navarro, Antonio Vargas, Patricia Rivera, Carlos Sanjuan, Fernando Rodríguez de Fonseca and Juan Suárez

Int. J. Mol. Sci. 2021, 22(10), 5365; https://doi.org/10.3390/ijms22105365 - 20 May 2021

Cited by 20 | Viewed by 5717

Abstract

Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer’s disease (AD). Late AD is associated with amyloid (Aβ) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg^5xFAD/5xFAD), heterozygous (Tg^5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aβ plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg^5xFAD/- and Tg^5xFAD/5xFAD mice and increased expression of IL-1β in Tg^5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg^5xFAD/- and Tg^5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development. Full article

(This article belongs to the Special Issue Hypothalamic Regulation of Obesity)

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13 pages, 4986 KiB

Open AccessArticle

Effects of Overexpression of Neurosecretory Protein GL-Precursor Gene on Glucose Homeostasis and Insulin Sensitivity in Mice

by Keisuke Fukumura, Yuki Narimatsu, Shogo Moriwaki, Eiko Iwakoshi-Ukena, Megumi Furumitsu and Kazuyoshi Ukena

Int. J. Mol. Sci. 2021, 22(9), 4681; https://doi.org/10.3390/ijms22094681 - 28 Apr 2021

Cited by 7 | Viewed by 2388

Abstract

A high-fat diet (HFD) quickly induces obesity with insulin resistance and hyperglycemia. We previously reported that a novel hypothalamic small protein, named neurosecretory protein GL (NPGL), stimulates feeding and fat accumulation in mice. However, the effects of NPGL on insulin sensitivity and glucose homeostasis remain unknown. Hence, we subjected NPGL-precursor gene (Npgl)-overexpressing mice to the oral glucose tolerance test (OGTT) and intraperitoneal insulin tolerance test (IPITT) under normal chow (NC) and HFD conditions. Npgl overexpression promoted body mass gain and tended to increase food intake of NC-fed mice, whereas it had little effect on HFD-fed mice. The OGTT showed elevated blood glucose and insulin levels in Npgl-overexpressing NC-fed mice 15 min after glucose administration. Both the OGTT and IPITT demonstrated that Npgl overexpression decreased blood glucose levels in HFD-fed mice 60 min after glucose and insulin treatments. Notably, Npgl overexpression increased adipose tissue masses only in NC-fed mice, and it decreased blood glucose and insulin levels in HFD-fed mice at the experimental end point. It also increased the mRNA expression of galanin, one of the feeding and metabolic regulatory neuropeptides, in the hypothalamus of HFD-fed mice. Therefore, NPGL may alleviate HFD-induced hyperglycemia and insulin resistance in mice. Full article

(This article belongs to the Special Issue Hypothalamic Regulation of Obesity)

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11 pages, 1712 KiB

Open AccessArticle

Angiopoietin-Like Growth Factor Involved in Leptin Signaling in the Hypothalamus

by Yunseon Jang, Jun Young Heo, Min Joung Lee, Jiebo Zhu, Changjun Seo, Da Hyun Go, Sung Kyung Yoon, Date Yukari, Yuichi Oike, Jong-Woo Sohn, Minho Shong and Gi Ryang Kweon

Int. J. Mol. Sci. 2021, 22(7), 3443; https://doi.org/10.3390/ijms22073443 - 26 Mar 2021

Cited by 3 | Viewed by 2579

Abstract

The hypothalamic regulation of appetite governs whole-body energy balance. Satiety is regulated by endocrine factors including leptin, and impaired leptin signaling is associated with obesity. Despite the anorectic effect of leptin through the regulation of the hypothalamic feeding circuit, a distinct downstream mediator of leptin signaling in neuron remains unclear. Angiopoietin-like growth factor (AGF) is a peripheral activator of energy expenditure and antagonizes obesity. However, the regulation of AGF expression in brain and localization to mediate anorectic signaling is unknown. Here, we demonstrated that AGF is expressed in proopiomelanocortin (POMC)-expressing neurons located in the arcuate nucleus (ARC) of the hypothalamus. Unlike other brain regions, hypothalamic AGF expression is stimulated by leptin-induced signal transducers and activators of transcription 3 (STAT3) phosphorylation. In addition, leptin treatment to hypothalamic N1 cells significantly enhanced the promoter activity of AGF. This induction was abolished by the pretreatment of ruxolitinib, a leptin signaling inhibitor. These results indicate that hypothalamic AGF expression is induced by leptin and colocalized to POMC neurons. Full article

(This article belongs to the Special Issue Hypothalamic Regulation of Obesity)

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17 pages, 11078 KiB

Open AccessArticle

Adiponectin Controls Nutrient Availability in Hypothalamic Astrocytes

by Nuri Song, Da Yeon Jeong, Thai Hien Tu, Byong Seo Park, Hye Rim Yang, Ye Jin Kim, Jae Kwang Kim, Joon Tae Park, Jung-Yong Yeh, Sunggu Yang and Jae Geun Kim

Int. J. Mol. Sci. 2021, 22(4), 1587; https://doi.org/10.3390/ijms22041587 - 4 Feb 2021

Cited by 12 | Viewed by 3166

Abstract

Adiponectin, an adipose tissue-derived hormone, plays integral roles in lipid and glucose metabolism in peripheral tissues, such as the skeletal muscle, adipose tissue, and liver. Moreover, it has also been shown to have an impact on metabolic processes in the central nervous system. Astrocytes comprise the most abundant cell type in the central nervous system and actively participate in metabolic processes between blood vessels and neurons. However, the ability of adiponectin to control nutrient metabolism in astrocytes has not yet been fully elucidated. In this study, we investigated the effects of adiponectin on multiple metabolic processes in hypothalamic astrocytes. Adiponectin enhanced glucose uptake, glycolytic processes and fatty acid oxidation in cultured primary hypothalamic astrocytes. In line with these findings, we also found that adiponectin treatment effectively enhanced synthesis and release of monocarboxylates. Overall, these data suggested that adiponectin triggers catabolic processes in astrocytes, thereby enhancing nutrient availability in the hypothalamus. Full article

(This article belongs to the Special Issue Hypothalamic Regulation of Obesity)

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Review

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22 pages, 1489 KiB

Open AccessReview

New Insights of SF1 Neurons in Hypothalamic Regulation of Obesity and Diabetes

by Anna Fosch, Sebastián Zagmutt, Núria Casals and Rosalía Rodríguez-Rodríguez

Int. J. Mol. Sci. 2021, 22(12), 6186; https://doi.org/10.3390/ijms22126186 - 8 Jun 2021

Cited by 19 | Viewed by 7759

Abstract

Despite the substantial role played by the hypothalamus in the regulation of energy balance and glucose homeostasis, the exact mechanisms and neuronal circuits underlying this regulation remain poorly understood. In the last 15 years, investigations using transgenic models, optogenetic, and chemogenetic approaches have revealed that SF1 neurons in the ventromedial hypothalamus are a specific lead in the brain’s ability to sense glucose levels and conduct insulin and leptin signaling in energy expenditure and glucose homeostasis, with minor feeding control. Deletion of hormonal receptors, nutritional sensors, or synaptic receptors in SF1 neurons triggers metabolic alterations mostly appreciated under high-fat feeding, indicating that SF1 neurons are particularly important for metabolic adaptation in the early stages of obesity. Although these studies have provided exciting insight into the implications of hypothalamic SF1 neurons on whole-body energy homeostasis, new questions have arisen from these results. Particularly, the existence of neuronal sub-populations of SF1 neurons and the intricate neurocircuitry linking these neurons with other nuclei and with the periphery. In this review, we address the most relevant studies carried out in SF1 neurons to date, to provide a global view of the central role played by these neurons in the pathogenesis of obesity and diabetes. Full article

(This article belongs to the Special Issue Hypothalamic Regulation of Obesity)

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13 pages, 855 KiB

Open AccessReview

Hypothalamic Astrocytes as a Specialized and Responsive Cell Population in Obesity

by Ismael González-García and Cristina García-Cáceres

Int. J. Mol. Sci. 2021, 22(12), 6176; https://doi.org/10.3390/ijms22126176 - 8 Jun 2021

Cited by 24 | Viewed by 4833

Abstract

Astrocytes are a type of glial cell anatomically and functionally integrated into the neuronal regulatory circuits for the neuroendocrine control of metabolism. Being functional integral compounds of synapses, astrocytes are actively involved in the physiological regulatory aspects of metabolic control, but also in the pathological processes that link neuronal dysfunction and obesity. Between brain areas, the hypothalamus harbors specialized functional circuits that seem selectively vulnerable to metabolic damage, undergoing early cellular rearrangements which are thought to be at the core of the pathogenesis of diet-induced obesity. Such changes in the hypothalamic brain region consist of a rise in proinflammatory cytokines, the presence of a reactive phenotype in astrocytes and microglia, alterations in the cytoarchitecture and synaptology of hypothalamic circuits, and angiogenesis, a phenomenon that cannot be found elsewhere in the brain. Increasing evidence points to the direct involvement of hypothalamic astrocytes in such early metabolic disturbances, thus moving the study of these glial cells to the forefront of obesity research. Here we provide a comprehensive review of the most relevant findings of molecular and pathophysiological mechanisms by which hypothalamic astrocytes might be involved in the pathogenesis of obesity. Full article

(This article belongs to the Special Issue Hypothalamic Regulation of Obesity)

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35 pages, 929 KiB

Open AccessReview

The Microbiota and the Gut–Brain Axis in Controlling Food Intake and Energy Homeostasis

by Marina Romaní-Pérez, Clara Bullich-Vilarrubias, Inmaculada López-Almela, Rebeca Liébana-García, Marta Olivares and Yolanda Sanz

Int. J. Mol. Sci. 2021, 22(11), 5830; https://doi.org/10.3390/ijms22115830 - 29 May 2021

Cited by 51 | Viewed by 10312

Abstract

Obesity currently represents a major societal and health challenge worldwide. Its prevalence has reached epidemic proportions and trends continue to rise, reflecting the need for more effective preventive measures. Hypothalamic circuits that control energy homeostasis in response to food intake are interesting targets for body-weight management, for example, through interventions that reinforce the gut-to-brain nutrient signalling, whose malfunction contributes to obesity. Gut microbiota–diet interactions might interfere in nutrient sensing and signalling from the gut to the brain, where the information is processed to control energy homeostasis. This gut microbiota–brain crosstalk is mediated by metabolites, mainly short chain fatty acids, secondary bile acids or amino acids-derived metabolites and subcellular bacterial components. These activate gut–endocrine and/or neural-mediated pathways or pass to systemic circulation and then reach the brain. Feeding time and dietary composition are the main drivers of the gut microbiota structure and function. Therefore, aberrant feeding patterns or unhealthy diets might alter gut microbiota–diet interactions and modify nutrient availability and/or microbial ligands transmitting information from the gut to the brain in response to food intake, thus impairing energy homeostasis. Herein, we update the scientific evidence supporting that gut microbiota is a source of novel dietary and non-dietary biological products that may beneficially regulate gut-to-brain communication and, thus, improve metabolic health. Additionally, we evaluate how the feeding time and dietary composition modulate the gut microbiota and, thereby, the intraluminal availability of these biological products with potential effects on energy homeostasis. The review also identifies knowledge gaps and the advances required to clinically apply microbiome-based strategies to improve the gut–brain axis function and, thus, combat obesity. Full article

(This article belongs to the Special Issue Hypothalamic Regulation of Obesity)

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33 pages, 5603 KiB

Open AccessReview

Adaptive Changes in the Central Control of Energy Homeostasis Occur in Response to Variations in Energy Status

by Cassandra Gastelum, Lynnea Perez, Jennifer Hernandez, Nikki Le, Isabella Vahrson, Sarah Sayers and Edward J. Wagner

Int. J. Mol. Sci. 2021, 22(5), 2728; https://doi.org/10.3390/ijms22052728 - 8 Mar 2021

Cited by 16 | Viewed by 5053

Abstract

Energy homeostasis is regulated in coordinate fashion by the brain-gut axis, the homeostatic energy balance circuitry in the hypothalamus and the hedonic energy balance circuitry comprising the mesolimbcortical A₁₀ dopamine pathway. Collectively, these systems convey and integrate information regarding nutrient status and the rewarding properties of ingested food, and formulate it into a behavioral response that attempts to balance fluctuations in consumption and food-seeking behavior. In this review we start with a functional overview of the homeostatic and hedonic energy balance circuitries; identifying the salient neural, hormonal and humoral components involved. We then delve into how the function of these circuits differs in males and females. Finally, we turn our attention to the ever-emerging roles of nociceptin/orphanin FQ (N/OFQ) and pituitary adenylate cyclase-activating polypeptide (PACAP)—two neuropeptides that have garnered increased recognition for their regulatory impact in energy homeostasis—to further probe how the imposed regulation of energy balance circuitry by these peptides is affected by sex and altered under positive (e.g., obesity) and negative (e.g., fasting) energy balance states. It is hoped that this work will impart a newfound appreciation for the intricate regulatory processes that govern energy homeostasis, as well as how recent insights into the N/OFQ and PACAP systems can be leveraged in the treatment of conditions ranging from obesity to anorexia. Full article

(This article belongs to the Special Issue Hypothalamic Regulation of Obesity)

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23 pages, 2807 KiB

Open AccessReview

Hypothalamic Microglial Heterogeneity and Signature under High Fat Diet–Induced Inflammation

by Natália Ferreira Mendes, Carlos Poblete Jara, Ariane Maria Zanesco and Eliana Pereira de Araújo

Int. J. Mol. Sci. 2021, 22(5), 2256; https://doi.org/10.3390/ijms22052256 - 24 Feb 2021

Cited by 16 | Viewed by 5132

Abstract

Under high-fat feeding, the hypothalamus atypically undergoes pro-inflammatory signaling activation. Recent data from transcriptomic analysis of microglia from rodents and humans has allowed the identification of several microglial subpopulations throughout the brain. Numerous studies have clarified the roles of these cells in hypothalamic inflammation, but how each microglial subset plays its functions upon inflammatory stimuli remains unexplored. Fortunately, these data unveiling microglial heterogeneity have triggered the development of novel experimental models for studying the roles and characteristics of each microglial subtype. In this review, we explore microglial heterogeneity in the hypothalamus and their crosstalk with astrocytes under high fat diet–induced inflammation. We present novel currently available ex vivo and in vivo experimental models that can be useful when designing a new research project in this field of study. Last, we examine the transcriptomic data already published to identify how the hypothalamic microglial signature changes upon short-term and prolonged high-fat feeding. Full article

(This article belongs to the Special Issue Hypothalamic Regulation of Obesity)

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11 pages, 844 KiB

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Hypothalamic Actions of SIRT1 and SIRT6 on Energy Balance

by Mar Quiñones, Eva Martínez-Grobas, Johan Fernø, Raquel Pérez-Lois, Luisa María Seoane and Omar Al Massadi

Int. J. Mol. Sci. 2021, 22(3), 1430; https://doi.org/10.3390/ijms22031430 - 31 Jan 2021

Cited by 17 | Viewed by 3669

Abstract

Sirtuins are NAD+ dependent deacetylases that regulate a large number of physiological processes. These enzymes are highly conserved and act as energy sensors to coordinate different metabolic responses in a controlled manner. At present, seven mammalian sirtuins (SIRT 1-7) have been identified, with SIRT1 and SIRT6 shown to exert their metabolic actions in the hypothalamus, both with crucial roles in eliciting responses to dampen metabolic complications associated with obesity. Therefore, our aim is to compile the current understanding on the role of SIRT1 and SIRT6 in the hypothalamus, especially highlighting their actions on the control of energy balance. Full article

(This article belongs to the Special Issue Hypothalamic Regulation of Obesity)

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Other

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16 pages, 1489 KiB

Open AccessPerspective

Microglia–Neuron Crosstalk in Obesity: Melodious Interaction or Kiss of Death?

by Stéphane Léon, Agnès Nadjar and Carmelo Quarta

Int. J. Mol. Sci. 2021, 22(10), 5243; https://doi.org/10.3390/ijms22105243 - 15 May 2021

Cited by 11 | Viewed by 4375

Abstract

Diet-induced obesity can originate from the dysregulated activity of hypothalamic neuronal circuits, which are critical for the regulation of body weight and food intake. The exact mechanisms underlying such neuronal defects are not yet fully understood, but a maladaptive cross-talk between neurons and surrounding microglial is likely to be a contributing factor. Functional and anatomical connections between microglia and hypothalamic neuronal cells are at the core of how the brain orchestrates changes in the body’s metabolic needs. However, such a melodious interaction may become maladaptive in response to prolonged diet-induced metabolic stress, thereby causing overfeeding, body weight gain, and systemic metabolic perturbations. From this perspective, we critically discuss emerging molecular and cellular underpinnings of microglia–neuron communication in the hypothalamic neuronal circuits implicated in energy balance regulation. We explore whether changes in this intercellular dialogue induced by metabolic stress may serve as a protective neuronal mechanism or contribute to disease establishment and progression. Our analysis provides a framework for future mechanistic studies that will facilitate progress into both the etiology and treatments of metabolic disorders. Full article

(This article belongs to the Special Issue Hypothalamic Regulation of Obesity)

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