Hypothalamic GABRA5-positive Neurons Control Obesity via Astrocytic GABA

Abstract

SUMMARYThe lateral hypothalamic area (LHA) regulates food intake and energy expenditure. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we identify that Gabra5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity (DIO) mouse model. Chemogenetic inhibition of GABRA5LHA suppresses energy expenditure and increases weight gain, whereas gene-silencing of Gabra5 in LHA decreases weight gain. In DIO mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by MAOB. Gene-silencing of astrocytic MAOB in LHA reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a MAOB inhibitor, KDS2010. We propose that firing of GABRA5LHA facilitates energy expenditure and selective inhibition of astrocytic GABA is a molecular target for treating obesity.

Role of Hypothalamic Reactive Astrocytes in Diet-Induced Obesity

“…Astrocyte reactivity is observed in various pathological contexts under acute or chronic conditions and, in many situations, is reversible ( Escartin et al, 2019 ; 2021 ). Reactive astrocytes are defined as astrocytes that undergo morphological, molecular, and functional remodeling in response to injury, disease, or infection of CNS, including neurodegenerative and demyelinating diseases, epilepsy, trauma, ischemia, infection, cancer, and obesity ( Bedner et al, 2015 ; Brusilow et al, 2010 ; Buckman et al, 2013 ; Escartin et al, 2019 ; 2021 ; Garcia-Caceres et al, 2019 ; Michetti et al, 2019 ; Sa et al, 2022 ; Verkhratsky et al, 2017 ; Xu et al, 2010 ). Glial fibrillary acidic protein (GFAP) is a major protein constituent of astrocytic intermediate filaments and the most widely used marker of reactive astrocytes ( Ben Haim et al, 2015 ; Eng and Ghirnikar, 1994 ).…”

“…In Wistar rats fed with HFD for 8 weeks, it has been consistently found that apoptosis is significantly increased, whereas synaptic input is significantly decreased in LHA ( Moraes et al, 2009 ). Moreover, neuronal dysfunction and decreased neuronal activity after chronic HFD exposure have been reported ( Moraes et al, 2009 ; Sa et al, 2022 ). Recently, a unique population of GABRA5-positive neurons in LHA has been discovered, and these neurons display pacemaker firing activity, which is decreased after HFD feeding in LHA ( Sa et al, 2022 ).…”

“…Moreover, neuronal dysfunction and decreased neuronal activity after chronic HFD exposure have been reported ( Moraes et al, 2009 ; Sa et al, 2022 ). Recently, a unique population of GABRA5-positive neurons in LHA has been discovered, and these neurons display pacemaker firing activity, which is decreased after HFD feeding in LHA ( Sa et al, 2022 ). These GABRA5-positive neurons are tonically inhibited by astrocytic GABA, which is synthesized by monoamine oxidase-B (MAOB) in reactive astrocytes ( Lee et al, 2010 ; Sa et al, 2022 ; Yoon et al, 2014 ).…”

“…Lastly, DMH cholinergic neurons increase food intake ( Jeong et al, 2017 ), whereas TrkB-expressing neurons suppress food intake ( Liao et al, 2019 ). When animals are challenged by high-fat diet (HFD) feeding, neurons that are homeostatically regulated in the hypothalamus lose metabolic control ( Moraes et al, 2009 ) and start to show dysfunctional firing patterns and distorted regulation by neurotransmitters and neurohormones ( Beutler et al, 2020 ; Sa et al, 2022 ). It has been further reported that with chronic feeding of 20 weeks of HFD, markers of neuronal injury become evident in the neurons of the hypothalamus ( Thaler et al, 2012 ).…”

“…Increasing lines of evidence suggests that elevated levels of GABA from reactive astrocytes act as a common molecular mechanism in other neuroinflammatory diseases, such as Alzheimer’s disease, Parkinson’s disease, white matter stroke, inflammation-induced anxiety, and epilepsy ( Chun et al, 2020 ; Heo et al, 2020 ; Jo et al, 2014 ; Nam et al, 2020 ; Pandit et al, 2020 ; Shim et al, 2019 ). Recently, GABA from hypothalamic reactive astrocytes under chronic HFD has been shown to contribute to the pathology of obesity by inhibiting the excitability of neighboring neurons facilitating energy expenditure ( Sa et al, 2022 ). In this review, we summarize recent discoveries related to the causes of reactive astrogliosis and the consequences of reactive astrocytes in the hypothalamus in an attempt to gain insights into the interplay between reactive astrocytes and neurons under DIO.…”