Diet-induced obesity (DIO) drastically increases susceptibility to the development of metabolic, cardiovascular, and neurological diseases, as well as the recent coronavirus disease (Kahn et al., 2006; Ren et al., 2021; Clemmensen et al., 2020; Xia et al., 2021; Benito-León et al., 2013). Leptin, a hormone secreted by white adipocytes, interacts with receptors in the brain to communicate peripheral fuel status, suppress appetite following a meal, promote energy expenditure, and maintain blood glucose stability (Friedman, 2009; Friedman, 2014; Flak and Myers, 2016; Friedman, 2019; Knight et al., 2010; Berglund et al., 2012; Caron et al., 2018). One of the key pathological characteristics of DIO is impaired metabolic homeostasis (Considine et al., 1995; Maffei et al., 1995). There is much evidence that central leptin signaling plays a vital role in the regulation of body weight, primarily via action within the arcuate nucleus (ARC)(Friedman, 2014; Flak and Myers, 2016; Minokoshi et al., 2002; Huynh et al., 2010; Pereira et al., 2019; Xu et al., 2018; Varela and Horvath, 2012; Vong et al., 2011). The long-form leptin receptors are abundantly expressed in the agouti-related protein (AgRP) neurons of the ARC (Xu et al., 2018; Baskin et al., 1999; Xu and Xie, 2016; Scott et al., 2009; Scott et al., 2011). Previous studies demonstrate that, under the physiological condition, leptin directly inhibits leptin receptor (LepR)-expressing AgRP neurons (Cowley et al., 2001; van den Top et al., 2004). However, clinical studies suggest that treatment of leptin in common obese patients has limited efficacy (Heymsfield et al., 1999; Farr et al., 2015; Hinney et al., 2022). The neural-circuit and transmitter-signaling mechanisms underlying leptin-mediated control of body weight and energy balance are not established.

AgRP neurons play fundamental roles in regulating feeding behavior and body weight by releasing inhibitory neuropeptide Y (NPY), AgRP and GABA transmitters into many downstream brain areas (Kishi and Elmquist, 2005; Han et al., 2021b; Xia et al., 2021). The afferents to these AgRP neurons and their postsynaptic targets have been identified as key players in the regulation of energy balance and systemic insulin sensitivity (Myers et al., 2009; Gropp et al., 2005; Luquet et al., 2005; Aponte et al., 2011; Könner et al., 2007; Steculorum et al., 2016). Leptin acts to decrease food intake and promote energy expenditure by suppressing the activity of AgRP neurons (Cowley et al., 2001; van den Top et al., 2004; Halaas et al., 1997; Friedman and Halaas, 1998). Selective ablation of LepR in AgRP neurons gives rise to an obese phenotype and diabetes (Xu et al., 2018; van de Wall et al., 2008). Although the LepR signaling within AgRP neurons has been implicated as the dominant component for the regulation of metabolic homeostasis, the underlying neural circuit mechanism is still poorly understood. We hypothesize that identification of the critical transmitter signaling components underlying the leptin-responsive neural circuit is crucial for the development of more efficient therapeutics for obesity.

Emerging data suggest a critical role of GABA signaling on the control of feeding behavior and energy homeostasis (Vong et al., 2011; Cone, 2005; Meister, 2007; Morton et al., 2006; Saper et al., 2002; Wu and Palmiter, 2011; Liu et al., 2012; Wu et al., 2013; Wu et al., 2009; Wu et al., 2012; Rossi and Stuber, 2018; Richard, 2015; Meng et al., 2016; Garfield et al., 2016; Pool et al., 2014; Cai et al., 2014; Krashes et al., 2013). Numerous studies suggest that central GABA_A- and GABA_B-receptor signaling exert prominent influences on feeding behavior under various metabolic states (Berridge, 2009; Cooper, 2005; Duke et al., 2006; Martire et al., 2010; Peciña and Berridge, 1996; Strader et al., 1997; Berner et al., 2009). For example, pharmacological activation of GABA_A-receptor signaling in the hindbrain parabrachial nucleus (PBN) enhances the positive hedonic perception of tastes and foods, thereby promoting food intake and motivational response to food reward (Berridge, 2009; Cooper, 2005; Peciña and Berridge, 1996; Berridge and Peciña, 1995; Higgs and Cooper, 1996; Söderpalm and Berridge, 2000; Berridge and Treit, 1986). Utilizing advanced genetic techniques, we have shown that GABAergic signaling from AgRP neurons plays a bidirectional, post-developmental role in the regulation of food intake and body weight (Meng et al., 2016). Our recent work shows that the α5-containing GABA_A receptor signaling within the bed nucleus of the stria terminalis neurons reciprocally regulates mental disorders and obesity, implying that GABA_A-receptor signaling exerts a role in controlling obesity and comorbid diseases (Xia et al., 2021).

In this report, we examined the neural-circuit mechanism underlying leptin action upon the AgRP neurons using a newly established and robust method of rapid inactivation of LepR signaling within AgRP neurons (Meng et al., 2016). We found that the LepR in AgRP neurons plays a pivotal role in the control of obesity and glucose homeostasis. Moreover, a subset of leptin-responsive AgRP neurons send GABAergic projections to a group of α3-containing GABA_A-expressing neurons in the DMH for regulation of leptin-mediated metabolic homeostasis. These findings suggest that the identification of key GABA_A signaling pathways within the post-synaptic target of a novel leptin-responsive GABAergic neural circuit forebode more efficient treatments for obesity.

To test the role of LepR in AgRP neurons, we applied our newly developed conditional knockout approach by generating two different lines of mice: Agrp^nsCre/+::Lepr^lox/lox::Neo^R::Rosa26^fs-tdTomato mice, termed the knockout group (Agrp-Lepr KO), and Agrp^+/+::Lepr^lox/lox::Neo^R::Rosa26^fs-tdTomato mice, termed the control group (Meng et al., 2016). Immunohistochemistry and qPCR results showed the expression of tdTomato and deletion of Lepr in AgRP neurons 4 days after treatment of NB124, a synthetic nonsense-suppressor that can rapidly restore the function of Cre recombinase within the AgRP neurons (Figure 1A–F and Figure 1—figure supplement 1). Agrp-Lepr KO mice showed a significant increase in feeding and body weight one week after deletion of LepR signaling from AgRP neurons (Figure 1G and H). As a recapitulation of the severe hyperphagia caused by CRISPR-mediated LepR deletion (Xu et al., 2018), our Agrp-Lepr KO mice exhibited 44.5% increase in feeding as compared to the control mice. Furthermore, along with the increase of body weight and food intake, Agrp-Lepr KO mice exhibited impaired glucose tolerance (Figure 1I). Leptin induces phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). pSTAT3 staining in the ARC showed enhanced extent in control mice but not in Agrp-Lepr KO mice 1  hr after leptin treatment in overnight fasted mice (Figure 1—figure supplement 2), indicating the role of leptin in the ARC was ablated. No significant changes of pSTAT3 level were observed in the DMH and VMH of control and Agrp-Lepr KO mice (Figure 1—figure supplement 3). Intriguingly, chronic infusion of bicuculline (Bic, 1 ng, a GABA_A receptor antagonist) into the 3rd ventricle abolished the hyperphagia responses in Agrp-Lepr KO mice (Figure 1J), suggesting that facilitating the post-synaptic GABA_A signaling to the AgRP neural circuit is important in regulating leptin-mediated feeding. The feeding efficiency (body weight gain [mg]/kilocalorie consumed) was significantly higher in Agrp-Lepr KO mice but was rescued by infusion of Bic (Figure 1K). The expansion of white adipose tissue (WAT) was observed in Agrp-Lepr KO mice (Figure 1L). We observed a significant decrease in respiratory quotient (RQ) from the Agrp-Lepr KO mice that can be further normalized by infusion of GABA_A antagonist (Figure 1M). In line with other studies, these results suggest that GABA is a crucial signaling molecule by which AgRP neurons control adiposity and nutrient utilization (Wu et al., 2009; Wu et al., 2008a; Tong et al., 2008). The control and Agrp-Lepr KO mice were also analyzed for their glucose tolerance. Ablation of LepR in the AgRP neurons impaired glucose tolerance, which was fully restored by infusion of GABA_A antagonist (Figure 1N). These results indicate that leptin regulates feeding and energy metabolism via post-synaptic GABA_A signaling from AgRP neurons.

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To identify the key downstream targets of AgRP neurons that contribute to leptin-mediated responses, we examined the Npas4 expression in potential AgRP target neurons. Traditional immediate early genes are regulated by neuromodulators via cAMP, neurotrophins, and other paracrine factors, and their kinetics are relatively slow. In contrast, Npas4 has a more dynamic response to activity-dependent signaling via Ca²⁺, and it can be bidirectionally regulated by either excitatory or inhibitory input (Shepard et al., 2019). The qPCR results showed that rapid deletion of LepR signaling from AgRP neurons resulted in a significant decrease of Npas4 abundance within the DMH (Figure 2A). To identify the functional relevance of each downstream target to leptin signaling, we administered DT into neonatal Agrp^DTR mice to ablate all AgRP neurons and examined the neural activity of their downstream targets in response to leptin (Figure 2B; Luquet et al., 2007; Zimmer et al., 2019). Without ablation of AgRP neurons, leptin induced robust Fos expression in almost all major targets of AgRP neurons (Wu et al., 2009; Wu et al., 2012; Wu et al., 2008b). However, neonatal ablation of AgRP neurons significantly diminished the leptin-mediated Fos induction within post-synaptic neurons residing in the DMH (Figure 2C–F and Figure 2—figure supplement 1). These results suggest that the DMH could be the key downstream target that critically contributes to the regulation of leptin-mediated appetitive and metabolic responses. To further visualize the neural circuit from AgRP neurons to DMH, we injected a retrograde herpes simplex virus (HSV) encoding a red fluorescent protein (HSV-hEf1α-mCherry) into the DMH of Npy^GFP mice (Figure 2G). Both HSV-based retrograde tracing and cholera toxin subunit B (CTB)-based retrograde neuroanatomical tracing from the DMH showed that ~17% (CTB tracing) or 39% (HSV tracing) of AgRP neurons project to the DMH (Figure 2H–L and Figure 2—figure supplement 2).

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To establish a role of the DMH within the leptin-responsive AgRP neural circuit, we combined the transsynaptic tracer (WGA-ZsGreen) and whole-cell, patch-clamp recordings to facilitate electrophysiological analysis of neurons in the DMH that are innervated by AgRP neurons (Figure 3A and B; Han et al., 2021b; Han et al., 2021a; Xu et al., 2017; Xia et al., 2021). RNA in situ hybridization confirmed that ~78% of AgRP-targeted neurons in the DMH express melanocortin receptor 4 (MC4R) (Figure 3C and Figure 3—figure supplement 1). To test whether this connectivity was monosynaptic, we perfused tetrodotoxin (TTX) and 4-aminopyridine (4-AP) into the bath to remove any network activity. We observed that inhibitory postsynaptic currents (IPSCs) in the DMH neurons triggered by photostimulation of ChR2-expressing axonal terminals of AgRP neurons were fully blocked by Bic (Figure 3D and E), confirming that these terminals were releasing GABA. In the presence of DNQX (a competitive AMPA/kainate receptor antagonist), AP5 (a selective NMDA receptor antagonist) and Bic, photostimulation of the ChR2-expressing AgRP terminals resulted in inhibition of action potentials in postsynaptic ZsGreen-positive neurons of the DMH in a reversible manner with significant reduction of firing rate and resting membrane potential (Figure 3F–I). We further examined the effect of leptin on the firing of postsynaptic ZsGreen-positive neurons in the DMH. We found that systemic treatment of leptin significantly enhanced neural activities of DMH neurons (Figure 3J and K).

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The original data of firing rate and rest membrane potential from in vitro electrophysiological recording in Figure 3.

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To examine the role of the AgRP→DMH circuit in the regulation of feeding and glucose, we performed optogenetic manipulation in Agrp^Cre::Roas26^fs-ChR2 (Ai32) mice where ChR2-EYFP was selectively expressed in AgRP neurons and axonal terminals (Han et al., 2021b; Xia et al., 2021). Photostimulation of AgRP fibers in the DMH promoted feeding and impaired glucose tolerance (Figure 4A and B). We found that about 13% of DMH neurons could be sensitive to the activation of AgRP neurons (Figure 4—figure supplement 1). We did not observe significant changes of Fos expression in the ARC after activation of AgRP fiber in the DMH, which excludes the potential effects of activating AgRP neurons (Figure 4—figure supplement 1D, H and J). In contrast, photostimulation of post-synaptic MC4R^DMH neurons decreased feeding and improved glucose tolerance (Figure 4C and D). Bilateral infusion of Bic (4 ng) into the DMH of Agrp-Lepr KO mice with micro-osmotic pumps resulted in reduced feeding and a significant reduction of body weight, coupled with improved glucose tolerance (Figure 4E–G). Blockage of GABA_A receptor in the DMH significantly rescued the feeding efficiency, expansion of WAT, and the RQ profiles in Agrp-Lepr KO mice (Figure 4H–K). The effect of drug diffusion was examined by Fos expression in the DMH and the neighboring brain regions, showing no significant difference of Fos expression in these regions. (Figure 4—figure supplement 2). These results suggest that GABA_A receptor signaling in the DMH is critical for the feeding, body weight, and glucose tolerance regulated by LepR in AgRP neurons.

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To better understand the physiological responses of these GABAergic neurons in the context of feeding and glucose regulation, we employed an in vivo opto-tetrode system to reveal the dynamic activities of MC4R^DMH neurons (Han et al., 2021a). With the injection of AAV2-DIO-ChR2-GFP into the DMH of Mc4r^Cre mice, we could record the activity of DMH neurons and identify those that express MC4R by their short-latency response to photostimulation as well as by the identical waveforms of evoked and spontaneous spikes (Han et al., 2021a). We investigated the activities of MC4R^DMH neurons and non-MC4R^DMH neurons under chow diet and hyperglycemia conditions. A total of 16 MC4R^DMH neurons and 12 non-MC4R^DMH neurons were identified through optogenetic-invoked spikes. The results showed that 10 out of 16 identified MC4R neurons showed decreased firing rate during foraging (prior to meal initiation), with an average reduction of firing rate from 9.8 Hz to 5.1 Hz (Figure 4L, M and P). We also observed 10 out of 16 MC4R neurons that responded to the enhancement of blood glucose with a reduction of firing rate from 10.0 Hz to 7.1 Hz (Figure 4N, O and Q). These results are consistent with MC4R^DMH neurons’ mediation of foraging and glucose tolerance.

Our results showed that GABA_A receptors in the DMH are involved in the regulation of feeding and glucose tolerance; thus, we attempted to identify the key GABA_A receptor subunits that are functionally relevant to glucose and feeding regulation. Results of qPCR analysis showed that, among all major regulatory α subunits, the transcript level of Gabra3 (encoding GABA_A receptor α3 subunits) in the DMH neurons of Agrp-Lepr KO mice was the highest (Figure 5A). Immunostaining confirmed that α3-GABA_A was abundantly expressed within the DMH (Figure 5B). Our transsynaptic tracing study further confirmed that the α3-GABA_A signaling was highly co-localized within the post-synaptic targets of the AgRP→DMH neural circuit (Figure 5C–E). To understand the functional roles of α3-GABA_A signaling within DMH neurons for leptin-mediated feeding and glucose, Mc4r^Cre::Rosa26^fs-Cas9 mice were injected with AAV9-Gabra3^sgRNA-tdTomato into the DMH. We found that knockout of Gabra3 signaling in the MC4R^DMH neurons reduced feeding and body weight while glucose tolerance was significantly improved (Figure 5F–H and Figure 5—figure supplement 1). Deficiency in α3-GABA_A signaling also significantly decreased feeding efficiency and WAT (Figure 5I and J). A gain-of-function study showed that overexpression of α3-GABA_A within the same MC4R^DMH neurons manifested opposite phenotypes, including moderately increased feeding and body weight and significantly increased feeding efficiency and WAT adiposity (Figure 5F–J). Importantly, overexpression of α3-GABA_A in the DMH neurons blunted the actions of leptin on feeding, body weight, glucose tolerance, feeding efficiency, and WAT adiposity (Figure 5K–O). To determine the role of α3-GABA_A receptor signaling from the MC4R^DMH neurons in the regulation of feeding and glucose tolerance by activation of AgRP-DMH circuit, Npy^Flp::Mc4^Cre mice with were injected with AAV9-fDIO-ChR2-EYFP into the ARC, AAV9-DIO-Cas9-mCitrine and AAV9-Gabra3^sgRNA-tdTomato into the DMH of followed with implantation of optic fiber in the DMH. We found that knockout of Gabra3 signaling in the MC4R^DMH neurons abolished the enhancement of feeding and impairment of glucose tolerance during activation of AgRP-DMH circuit (Figure 5—figure supplement 2). These results suggest the AgRP-DMH circuit regulates feeding and glucose tolerance depending on the α3-GABA_A receptor signaling in the MC4R^DMH neurons. We further examined the effects of ablating α3-GABA_A in the DMH on feeding and body weight in diet-induced obese mice. We found that genetic deletion of Gabra3 signaling in the MC4R^DMH neurons led to a decrease in daily food consumption associated with a moderate weight loss and that these knockout mice showed reduced refeeding responses (Figure 5P–R). These results suggest that the MC4R^DMH neurons play a significant role in control of glucose tolerance and feeding through the α3-GABA_A signaling.

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Leptin exerts its behavioral and metabolic effects by modulating signaling of AgRP neurons that are susceptible to obesity-induced leptin resistance. In this report, we explored the neural circuit and transmitter-signaling mechanisms underlying leptin-mediated feeding and energy metabolism (Figure 5S). We identified and characterized a unique GABAergic neural circuit with functional significance: the neural circuit from LepR-expressing AgRP neurons to α3-GABA_A receptor expressing DMH neurons plays a critical role in the control of feeding, body weight and glucose tolerance through α3-GABA_A receptor signaling. This leptin-responsive neural circuit plays a fundamental role in the regulation of hyperphagia and metabolism in obesity, which suggests manipulation of the neural circuit pharmacologically could lead to novel obesity therapeutics.

This study utilized a newly established inducible-knockout strategy to achieve rapid, post-developmental, targeted inactivation of LepR signaling, which precisely illuminates the pathophysiological roles of central leptin signaling on the control of nutrient partitioning and feeding efficiency. Compared with the mild effects of the non-inducible manipulation of brain LepR signaling, our Agrp-Lepr KO model showed a robust disruption in various feeding and metabolism parameters, culminating in severe obesity, which was previously achieved by global genetic deletion or the CRISPR–Cas9 technique (Xu et al., 2018; van de Wall et al., 2008; Gonçalves et al., 2014; Egan et al., 2017). Our technique has many attractive features, such as the large repertoire of conditional mouse lines, transient and non-BBB-crossing inducer, and easy combination with numerous viral tools, that can be applied to many neurological and endocrine questions.

We applied HSV to map the AgRP-DMH circuit. HSV-hEF1α has been extensively used to retrogradely transport from the peripheral nerve terminals to the central nervous system through axonal transport (Fang et al., 2018; Tan et al., 2016; Eagle et al., 2020; Yamaguchi et al., 2020; Garcia et al., 2021; Gremel et al., 2016; Valentinova et al., 2019; Marcinkiewcz et al., 2016), while some applications take advantage of the anterograde capacity of other different strains for example HSV-H129 (Azevedo et al., 2019; Lo and Anderson, 2011). To further verify the AgRP-DMH circuit, we applied CTB which is capable of being taken up by neurons and transported in a retrograde direction towards the cell body. Consistent with HSV tracing results, CTB tracing strategy also showed the connection between AgRP neurons and DMH.

We applied pharmacological approaches to block GABA_A signaling within the AgRP-DMH circuit, which can blunt the hyperphagia responses and improve glucose intolerance in Agrp-Lepr KO mice. These results suggest that the GABA_A signaling system within the AgRP-DMH circuit exerts rapid actions on feeding behaviors and glucose metabolism. This shows the consistency that GABA in the AgRP neurons is required for the stimulation of feeding (Krashes et al., 2013). Furthermore, we observed decreased food intake and weight loss as a result of chronic blockage of GABA_A signaling in the DMH, indicating that GABA_A signaling within the AgRP-DMH circuit may also participate in the chronic regulation of feeding and body weight. On the other hand, some studies showed that AgRP neurons can chronically regulate feeding through the mechanism of long-term suppression over the downstream brain targets independent of GABA_A signaling (Krashes et al., 2013; Wang et al., 2021). Together, we suggest that the GABA signaling in the AgRP neurons may exert chronic effects on appetite and weight control via a distinct neural pathway from the co-released AgRP and NPY.

The profiling assay using neonatal ablation of AgRP neurons revealed key neural populations responding to leptin. Among various downstream targets of the AgRP circuit, the DMH neurons are the most sensitive to AgRP-dependent leptin signaling. Acute stimulation of post-synaptic MC4R neurons within the DMH blunted glucose tolerance and feeding.

The GABA_A subunits in the hypothalamus are involved in the regulation of feeding. We employed the CRISPR-Cas9, gene-editing method to comprehensively evaluate the function of GABA_A subunits α3 within a leptin-responsive neural circuit. Genetic deletion of α3 in the MC4R neurons in the DMH suppressed feeding and glucose tolerance. These studies demonstrate that the GABA_A subunits α3 within the secondary structure of the GABAergic neural circuit play an important role in the control of leptin-mediated hypometabolism and obesity.

Utilizing the in vivo optrode recording system, we performed stable intracellular recordings from MC4R neurons in the DMH in intact and awake mice, allowing us to study complex behaviors and physiological responses. Here, we focused on the effects of MC4R neurons in the DMH on sensing glucose levels. There are several brain regions such as ARC, LH, PVH, VMH, and DMH that could sense peripheral glucose levels including glucose-excited and glucose-inhibited neurons (Routh et al., 2014; Claret et al., 2007; He et al., 2020; Huang et al., 2022; Burdakov et al., 2005). Our results showed that 62.5% of MC4R neurons in the DMH neurons are relevant to hyperglycemia due to their suppressed neural activity associated with high glucose levels. Others showed either unresponsive or opposite phenotypes. Overall, the effects of glucose on MC4R neurons in the DMH suggest that glucose is a complex and dynamic metabolic signal that interacts with multiple neural circuits to regulate glucose homeostasis.

In conclusion, LepR in the AgRP neurons and the associated neural circuit and receptor are the primary mediators of leptin action in feeding and metabolic homeostasis. We suggest that new therapeutics selectively targeting α3-GABA_A associated signaling components within this GABAergic neural circuit would prevent obesity.

All data generated or analyzed during this study are included in the manuscript and supporting file.

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Author details

1. Yong Han

   USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0768-046X

2. Yang He

   USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

3. Lauren Harris

   USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States

   Contribution

   Methodology

   Competing interests

   No competing interests declared

4. Yong Xu

   USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States

   Contribution

   Resources, Funding acquisition

   Competing interests

   No competing interests declared

5. Qi Wu

   USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, United States

   Contribution

   Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   qiw@bcm.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-0303-4065

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