Arcuate Nucleus-Dependent Regulation of Metabolism—Pathways to Obesity and Diabetes Mellitus

Abstract

The central nervous system (CNS) receives information from afferent neurons, circulating hormones and absorbed nutrients and integrates this information to orchestrate the actions of the neuroendocrine and autonomic nervous systems in maintaining systemic metabolic homeostasis. Particularly the arcuate nucleus of the hypothalamus (ARC) is of pivotal importance for primary sensing of adiposity signals, such as leptin and insulin, and circulating nutrients, such as glucose. Importantly, energy state-sensing neurons in the ARC not only regulate feeding but at the same time control multiple physiological functions, such as glucose homeostasis, blood pressure and innate immune responses. These findings have defined them as master regulators, which adapt integrative physiology to the energy state of the organism. The disruption of this fine-tuned control leads to an imbalance between energy intake and expenditure as well as deregulation of peripheral metabolism. Improving our understanding of the cellular, molecular and functional basis of this regulatory principle in the CNS could set the stage for developing novel therapeutic strategies for the treatment of obesity and metabolic syndrome. In this review, we summarize novel insights with a particular emphasis on ARC neurocircuitries regulating food intake and glucose homeostasis and sensing factors that inform the brain of the organismal energy status.

Hypercaloric diet triggers transient molecular rearrangements of astrocytes selectively in the arcuate nucleus

“…Given that the ARC orchestrates whole-body energy metabolism (Jais and Brüning, 2021, González-García and García-Cáceres, 2021), and the morphology of ARC astrocytes is particularly affected by a hypercaloric diet (Thaler et al, 2012), we assessed the effects of a HFHS diet feeding over time on ARC-derived cells, to investigate their diet- and time-dependent transcriptomic modifications. Based on previous studies from our group showing that 15 days (d) of a HFHS diet exposure are sufficient to increase the body weight of mice in comparison to a standard chow (SC) diet (Gruber et al, 2021), we selected two critical time points: 5 and 15d of exposure to a HFHS diet for the assessment.…”

“…Whether the population of a definite area in the ARC by astrocytes expressing specific molecular markers might correlate with an adaptive synaptic rearrangement or a pathological impairment in the neurotransmitter/ion homeostasis of surrounding neurons need to be further elucidated. Hypercaloric diet primarily promotes an aberrant neuronal activity specifically in the entangled circuits of the ARC (Kälin et al, 2015, Jais et al, 2020, Jais and Brüning, 2021. Thus, the increase in GFAP-and Aldh1L1-expressing astrocytes in this area may result from (or cause) specific adaptive responses of these glial cells to alterations in different neuronal and synaptic subtypes.…”

Hypothalamic pregnenolone mediates recognition memory in the context of metabolic disorders

“…Hypothalamic AgRP and POMC neurons are fundamental nexus for the physiological control of energy balance and glucose metabolism (Jais and Br€ uning, 2021). Thus, we conducted detailed metabolic phenotyping of AgRPStarKO and POMC-StarKO mice.…”

“…Despite receiving much less attention in the field of cognitive science, the hypothalamus is crucially positioned to connect metabolic status with cognition for diverse reasons. First, because distinct hypothalamic nuclei and neuronal types (namely, POMC and AgRP neurons) play fundamental roles in the regulation of systemic energy balance and in the development of obesity and T2D (Jais and Br€ uning, 2021). Second, because the hypothalamus has been historically related to memory disorders (Vercruysse et al, 2018), and third, because evidence from recent studies shows that it may act as an interface for diverse types of cognition (Burdakov and Peleg-Raibstein, 2020).…”

Diet-Induced Metabolic Dysfunction of Hypothalamic Nutrient Sensing in Rodents

“…The mediobasal hypothalamus (MBH) of the brain gathers information about the body’s nutritional status to implement appropriate behavioral and metabolic responses to changes in nutrient availability [ 4 , 5 , 6 , 8 ]. This information is relayed to the MBH through at least two ways [ 9 ]: (1) changes in the levels of hormones (such as insulin or leptin) that are controlled by nutrient availability and (2) changes in circulating macronutrients or their metabolites.…”