Background/Aims: Nesfatin-1, processed from nucleobindin-2 (NUCB2), is a potent anorexigenic peptide being expressed in rodent hypothalamic nuclei and involved in the regulation of feeding behavior and body weight in animals. The present study aimed to investigate NUCB2/nesfatin-1 protein expression in the human hypothalamus as well as its correlation with body weight. Methods: Sections of hypothalamus and adjacent cholinergic basal forebrain nuclei, including the nucleus basalis of Meynert (NBM) and the diagonal band of Broca (DBB), from 25 autopsy cases (17 males, 8 females; 8 lean, 9 overweight, 8 obese) were examined using immunohistochemistry and double immunofluorescence labeling. Results: Prominent NUCB2/nesfatin-1 immunoexpression was detected in supraoptic, paraventricular, and infundibular nuclei, lateral hypothalamic area (LHA)/perifornical region, and NBM/DBB. NUCB2/nesfatin-1 was found to extensively colocalize with (a) oxytocin and vasopressin in paraventricular and supraoptic nuclei, (b) melanin-concentrating hormone in the LHA, and (c) cocaine- and amphetamine-regulated transcript in infundibular and paraventricular nuclei and LHA. Interestingly, in the LHA, NUCB2/nesfatin-1 protein expression was significantly decreased in obese, compared with lean (p < 0.01) and overweight (p < 0.05) subjects. Conclusions: The findings of the present study are suggestive of a potential role for NUCB2/nesfatin-1 as an integral regulator of food intake and energy homeostasis in the human hypothalamus. In the LHA, an appetite- and reward-related brain area, reduced NUCB2/nesfatin-1 immunoexpression may contribute to dysregulation of homeostatic and/or hedonic feeding behavior and obesity. NUCB2/nesfatin-1 localization in NBM/DBB might imply its participation in the neuronal circuitry controlling cognitive influences on food intake and give impetus towards unraveling additional biological actions of NUCB2/nesfatin-1 in human neuronal networks.

Data on animals emphasize the importance of the neuronal glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) for feeding suppression, although it is unclear whether astrocytes participate in the transduction of anorectic GLP-1R-dependent signals. In humans, the brain circuitry underlying these effects remains insufficiently investigated. The present study aimed to explore GLP-1R protein expression in the human hypothalamus and its correlation with body mass index (BMI). Sections of hypothalamus from 28 autopsy cases, 11 with normal weight (BMI < 25 kg/m²) and 17 with non-normal weight (BMI ≥ 25 kg/m²), were examined using immunohistochemistry and double immunofluorescence labeling. Prominent GLP-1R immunoexpression was detected in neurons of several hypothalamic nuclei, including paraventricular, supraoptic, and infundibular nuclei; the lateral hypothalamic area (LH); and basal forebrain nuclei. Interestingly, in the LH, GLP-1R was significantly decreased in individuals with BMI ≥ 25 kg/m² compared with their normal weight counterparts (p = 0.03). Furthermore, GLP-1R was negatively correlated (τb = −0.347, p = 0.024) with BMI levels only in the LH. GLP-1R extensively colocalized with the anorexigenic and antiobesogenic neuropeptide nucleobindin-2/nesfatin-1 but not with the astrocytic marker glial fibrillary acidic protein. These data suggest a potential role for GLP-1R in the regulation of energy balance in the human hypothalamus. In the LH, an appetite- and reward-related brain region, reduced GLP-1R immunoexpression may contribute to the dysregulation of homeostatic and/or hedonic feeding behavior. Possible effects of NUCB2/nesfatin-1 on central GLP-1R signaling require further investigation.

Hypothalamic obesity represents a clinical condition within the broader spectrum of obesity that frequently eludes detection and appropriate diagnosis. This subset of obesity is characterized by a dearth of established predictive markers and a paucity of standardized therapeutic protocols. The advent and rising prominence of glucagon-like peptide-1 (GLP-1) receptor agonists in the obesity treatment landscape present novel therapeutic avenues for hypothalamic obesity management. Nonetheless, critical inquiries persist concerning the efficacy of GLP-1 receptor (GLP-1R) agonists in this context, particularly regarding their central mechanisms of action and specific impact on hypothalamic obesity. In this narrative review, we concentrate on analyzing research papers that delineate the detection and function of GLP-1 receptors across various hypothalamic and cerebral regions. Additionally, we examine clinical research papers and reports detailing the application of GLP-1 receptor agonists in treating hypothalamic obesity. Furthermore, we include a concise presentation of a clinical case from our unit for contextual understanding. Currently, the clinical evidence supporting the efficacy of GLP-1 receptor agonists in hypothalamic obesity, as well as the diverse characteristics of this obesity subtype, remains insufficient. Preliminary data suggest that GLP-1R agonists might offer an effective treatment option, albeit with variable outcomes, particularly in younger patient cohorts. From a mechanistic perspective, the presence of GLP-1 receptors in various hypothalamic and broader brain regions potentially underpins the efficacy of GLP-1R agonists, even in instances of hypothalamic damage. Nevertheless, additional research is imperative to establish the functional relevance of these receptors in said brain regions. GLP-1R agonists represent a potential therapeutic option for patients with hypothalamic obesity. However, further clinical and basic/translational research is essential to validate the efficacy of these drugs across different presentations of hypothalamic obesity and to understand the functionality of GLP-1R in the diverse brain regions where they are expressed.

Introduction: Glucagon-like peptide-1 (GLP-1) anorexigenic and anti-obesogenic effects are centrally mediated. Data on animals emphasize the importance of neuronal GLP-1 receptor (GLP-1R) for feeding suppression, although it is unclear whether astrocytes participate in the transduction of anorectic GLP-1R-dependent signals. In humans, the brain circuitry underlying these effects remains insufficiently investigated. GLP-1R neuroanatomic localization in human hypothalamus, a brain region with a pivotal role in energy homeostasis regulation, is essential in order to improve our understanding of GLP-1 signaling pathways and central metabolic functions. The present study aimed to explore GLP-1R protein expression in human hypothalamus and its correlation with body mass index (BMI). Methods: Sections of hypothalamus from 28 autopsy cases, 11 with normal weight (BMI < 25 Kg/m ² ) and 17 with non-normal weight (BMI ≥ 25 Kg/m ² ), were examined using immunohistochemistry and double immunofluorescence labeling. Results: Prominent GLP-1R immunoexpression was detected in neurons of several hypothalamic nuclei, including paraventricular, supraoptic, and infundibular nuclei, lateral hypothalamic area (LH), and basal forebrain nuclei. Interestingly, in LH, GLP-1R protein expression was significantly decreased in individuals with BMI ≥ 25 Kg/m2, compared with normal weight counterparts (p=0.03). Furthermore, GLP-1R was moderately and negatively correlated (τb=-0.347, p=0.024) with BMI levels only in the LH. GLP-1R extensively colocalized with the anorexigenic and anti-obesogenic neuropeptide nucleobindin-2/nesfatin-1, but not with the astrocytic marker glial fibrillary acidic protein (GFAP). Conclusion: These data suggest a potential role for GLP-1R in the regulation of energy balance in human hypothalamus, possibly through interactions with nesfatin-1. In LH, an appetite- and reward-related brain region, reduced GLP-1R immunoexpression may contribute to dysregulation of homeostatic and/or hedonic feeding behavior. GLP-1R colocalization with nesfatin-1 in the basal forebrain, a cognition-related brain area, might give impetus towards elucidating additional central actions of GLP-1R.

Maternal obesity disrupts fetal hypothalamic development by inducing structural changes in feeding circuits, such as reduced hypothalamic precursor proliferation, blunted energy-status sensing, and aberrant wiring of melanocortin pathways, ultimately promoting long-term obesity risk in offspring. Although this hypothalamic reprogramming has dominated research, emerging evidence supports a broader, distributed model involving both brainstem interoceptive circuits and mesocorticolimbic reward-control systems. Maternal obesity is associated with impaired white matter development in offspring, as well as compromised functional connectivity, abnormal orexigenic and anorexigenic signaling, hypothalamic inflammation, and epigenetic alterations in neurodevelopmental genes. Human neuroimaging studies demonstrate altered network connectivity in neonates associated with maternal adiposity. However, the mechanism through which dysregulated maternal signals ultimately reach and reprogram the developing brain remains largely elusive. The present review aims to elucidate the mechanisms by which maternal overnutrition drives the embryonic rewiring of feeding circuits beyond the hypothalamus, highlighting the susceptibility of these extra-hypothalamic neural networks to obesogenic programming. Future research should prioritize investigating the effects of maternal obesity on fetal cytoarchitecture and function in feeding-related neuroanatomical circuits, including brainstem interoceptive nuclei and mesocorticolimbic reward-control pathways. Elucidating these developmental neuro-metabolic changes may offer the opportunity to establish early intervention measures for preserving offspring metabolic health.