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Hypothalamic Regulation of Obesity and Diabetes
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Hypothalamic Regulation of Obesity and Diabetes

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

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 10376

Special Issue Editors

Dr. Rosalía Rodríguez-Rodríguez

E-Mail Website
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
Special Issues, Collections and Topics in MDPI journals
Dr. Cristina Miralpeix

E-Mail Website
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
Dr. Sebastian Zagmutt

E-Mail Website
Guest Editor
Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, Spain
Interests: obesity; hypothalamus

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 type-2 diabetes 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, glucose homeostasis and nutrient partitioning. Within the hypothalamus, numerous specialized neuronal populations are connected both to each other, and 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 and diabetes development. Novel findings related to key systems such as endocannabinoids, insulin 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. Therefore, here we will present an overview of the most recent mechanisms underlying the hypothalamic regulation of obesity and diabetes and the impact of these investigations in the prevention and treatment of human metabolic diseases.

Dr. Rosalía Rodríguez-Rodríguez
Dr. Cristina Miralpeix
Dr. Sebastian Zagmutt
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Published Papers (5 papers)

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Research

14 pages, 4091 KiB  
Article
Hypothalamic Reactivity and Connectivity following Intravenous Glucose Administration
by Joe J. Simon, Pia M. Lang, Lena Rommerskirchen, Martin Bendszus and Hans-Christoph Friederich
Int. J. Mol. Sci. 2023, 24(8), 7370; https://doi.org/10.3390/ijms24087370 - 17 Apr 2023
Cited by 1 | Viewed by 1217
Abstract
Dysfunctional glucose sensing in homeostatic brain regions such as the hypothalamus is interlinked with the pathogenesis of obesity and type 2 diabetes mellitus. However, the physiology and pathophysiology of glucose sensing and neuronal homeostatic regulation remain insufficiently understood. To provide a better understanding [...] Read more.
Dysfunctional glucose sensing in homeostatic brain regions such as the hypothalamus is interlinked with the pathogenesis of obesity and type 2 diabetes mellitus. However, the physiology and pathophysiology of glucose sensing and neuronal homeostatic regulation remain insufficiently understood. To provide a better understanding of glucose signaling to the brain, we assessed the responsivity of the hypothalamus (i.e., the core region of homeostatic control) and its interaction with mesocorticolimbic brain regions in 31 normal-weight, healthy participants. We employed a single-blind, randomized, crossover design of the intravenous infusion of glucose and saline during fMRI. This approach allows to investigate glucose signaling independent of digestive processes. Hypothalamic reactivity and connectivity were assessed using a pseudo-pharmacological design and a glycemia-dependent functional connectivity analysis, respectively. In line with previous studies, we observed a hypothalamic response to glucose infusion which was negatively related to fasting insulin levels. The observed effect size was smaller than in previous studies employing oral or intragastric administration of glucose, demonstrating the important role of the digestive process in homeostatic signaling. Finally, we were able to observe hypothalamic connectivity with reward-related brain regions. Given the small amount of glucose employed, this points toward a high responsiveness of these regions to even a small energy stimulus in healthy individuals. Our study highlights the intricate relationship between homeostatic and reward-related systems and their pronounced sensitivity to subtle changes in glycemia. Full article
(This article belongs to the Special Issue Hypothalamic Regulation of Obesity and Diabetes)
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18 pages, 6127 KiB  
Article
Central Regulation of Brown Fat Thermogenesis in Response to Saturated or Unsaturated Long-Chain Fatty Acids
by Anna Fosch, Maria Rodriguez-Garcia, Cristina Miralpeix, Sebastián Zagmutt, Maite Larrañaga, Ana Cristina Reguera, Jesus Garcia-Chica, Laura Herrero, Dolors Serra, Nuria Casals and Rosalia Rodriguez-Rodriguez
Int. J. Mol. Sci. 2023, 24(2), 1697; https://doi.org/10.3390/ijms24021697 - 15 Jan 2023
Cited by 3 | Viewed by 2307
Abstract
Sensing of long-chain fatty acids (LCFA) in the hypothalamus modulates energy balance, and its disruption leads to obesity. To date, the effects of saturated or unsaturated LCFA on hypothalamic-brown adipose tissue (BAT) axis and the underlying mechanisms have remained largely unclear. Our aim [...] Read more.
Sensing of long-chain fatty acids (LCFA) in the hypothalamus modulates energy balance, and its disruption leads to obesity. To date, the effects of saturated or unsaturated LCFA on hypothalamic-brown adipose tissue (BAT) axis and the underlying mechanisms have remained largely unclear. Our aim was to characterize the main molecular pathways involved in the hypothalamic regulation of BAT thermogenesis in response to LCFA with different lengths and degrees of saturation. One-week administration of high-fat diet enriched in monounsaturated FA led to higher BAT thermogenesis compared to a saturated FA-enriched diet. Intracerebroventricular infusion of oleic and linoleic acids upregulated thermogenesis markers and temperature in brown fat of mice, and triggered neuronal activation of paraventricular (PaV), ventromedial (VMH) and arcuate (ARC) hypothalamic nuclei, which was not found with saturated FAs. The neuron-specific protein carnitine palmitoyltransferase 1-C (CPT1C) was a crucial effector of oleic acid since the FA action was blunted in CPT1C-KO mice. Moreover, changes in the AMPK/ACC/malonyl-CoA pathway and fatty acid synthase expression were evoked by oleic acid. Altogether, central infusion of unsaturated but not saturated LCFA increases BAT thermogenesis through CPT1C-mediated sensing of FA metabolism shift, which in turn drive melanocortin system activation. These findings add new insight into neuronal circuitries activated by LCFA to drive thermogenesis. Full article
(This article belongs to the Special Issue Hypothalamic Regulation of Obesity and Diabetes)
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14 pages, 2986 KiB  
Article
TRIM67 Deficiency Exacerbates Hypothalamic Inflammation and Fat Accumulation in Obese Mice
by Lanlan Jia, Zhengli Chen, Ting Pan, Yu Xia, Junbo He, Asad Jahangir, Xiaoli Wei, Wentao Liu, Riyi Shi, Chao Huang and Qihui Luo
Int. J. Mol. Sci. 2022, 23(16), 9438; https://doi.org/10.3390/ijms23169438 - 21 Aug 2022
Cited by 3 | Viewed by 1800
Abstract
Obesity has achieved the appearance of a global epidemic and is a serious cause for concern. The hypothalamus, as the central regulator of energy homeostasis, plays a critical role in regulating food intake and energy expenditure. In this study, we show that TRIM67 [...] Read more.
Obesity has achieved the appearance of a global epidemic and is a serious cause for concern. The hypothalamus, as the central regulator of energy homeostasis, plays a critical role in regulating food intake and energy expenditure. In this study, we show that TRIM67 in the hypothalamus was responsive to body-energy homeostasis whilst a deficiency of TRIM67 exacerbated metabolic disorders in high-fat-diet-induced obese mice. We found exacerbated neuroinflammation and apoptosis in the hypothalamus of obese TRIM67 KO mice. We also found reduced BDNF in the hypothalamus, which affected the fat sympathetic nervous system innervation and contributed to lipid accumulation in adipose tissue under high-fat-diet exposure. In this study, we reveal potential implications between TRIM67 and the hypothalamic function responding to energy overuptake as well as a consideration for the therapeutic diagnosis of obesity. Full article
(This article belongs to the Special Issue Hypothalamic Regulation of Obesity and Diabetes)
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17 pages, 3792 KiB  
Article
Neurosecretory Protein GL Promotes Normotopic Fat Accumulation in Male ICR Mice
by Yuki Narimatsu, Daichi Matsuura, Eiko Iwakoshi-Ukena, Megumi Furumitsu and Kazuyoshi Ukena
Int. J. Mol. Sci. 2022, 23(12), 6488; https://doi.org/10.3390/ijms23126488 - 10 Jun 2022
Cited by 4 | Viewed by 1751
Abstract
Neurosecretory protein GL (NPGL) is a small secretory protein identified in the hypothalamus of birds and mammals. We recently reported that NPGL exerts obesogenic effects in obesity-prone C57BL6/J mice. However, whether NPGL elicits adiposity in different mouse strains is poorly understood. In this [...] Read more.
Neurosecretory protein GL (NPGL) is a small secretory protein identified in the hypothalamus of birds and mammals. We recently reported that NPGL exerts obesogenic effects in obesity-prone C57BL6/J mice. However, whether NPGL elicits adiposity in different mouse strains is poorly understood. In this study, we generated transgenic mice overexpressing Npgl using the ICR strain (Npgl Tg mice) to elucidate the obesogenic effects of NPGL in different strains. Npgl Tg mice showed increased white adipose tissue (WAT) mass. Although the mass of brown adipose tissue (BAT) was slightly altered in Npgl Tg mice, hypertrophy of lipid droplets was also observed in BAT. In contrast, fat accumulation was not induced in the liver, with the upregulation of mRNAs related to hepatic lipolysis. These results support the hypothesis that NPGL causes obesity in several strains and species. This report highlights the pivotal role of NPGL in fat accumulation in adipose tissues and contributes to the elucidation of the biological mechanisms underlying obesity and metabolic diseases in heterogeneous populations. Full article
(This article belongs to the Special Issue Hypothalamic Regulation of Obesity and Diabetes)
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17 pages, 2463 KiB  
Article
Insulin-like Growth Factor I Couples Metabolism with Circadian Activity through Hypothalamic Orexin Neurons
by Jaime Pignatelli, M. Estrella Fernandez de Sevilla, Jacob Sperber, Daniel Horrillo, Gema Medina-Gomez and Ignacio Torres Aleman
Int. J. Mol. Sci. 2022, 23(9), 4679; https://doi.org/10.3390/ijms23094679 - 23 Apr 2022
Cited by 4 | Viewed by 2211
Abstract
Uncoupling of metabolism and circadian activity is associated with an increased risk of a wide spectrum of pathologies. Recently, insulin and the closely related insulin-like growth factor I (IGF-I) were shown to entrain feeding patterns with circadian rhythms. Both hormones act centrally to [...] Read more.
Uncoupling of metabolism and circadian activity is associated with an increased risk of a wide spectrum of pathologies. Recently, insulin and the closely related insulin-like growth factor I (IGF-I) were shown to entrain feeding patterns with circadian rhythms. Both hormones act centrally to modulate peripheral glucose metabolism; however, whereas central targets of insulin actions are intensely scrutinized, those mediating the actions of IGF-I remain less defined. We recently showed that IGF-I targets orexin neurons in the lateral hypothalamus, and now we evaluated whether IGF-I modulates orexin neurons to align circadian rhythms with metabolism. Mice with disrupted IGF-IR activity in orexin neurons (Firoc mice) showed sexually dimorphic alterations in daily glucose rhythms and feeding activity patterns which preceded the appearance of metabolic disturbances. Thus, Firoc males developed hyperglycemia and glucose intolerance, while females developed obesity. Since IGF-I directly modulates orexin levels and hepatic expression of KLF genes involved in circadian and metabolic entrainment in an orexin-dependent manner, it seems that IGF-I entrains metabolism and circadian rhythms by modulating the activity of orexin neurons. Full article
(This article belongs to the Special Issue Hypothalamic Regulation of Obesity and Diabetes)
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