Author response: Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat

Beutler, Lisa R.; Corpuz, Timothy V; Ahn, Jamie S.; Kosar, Seher; Song, Weimin; Chen, Yiming; Knight, Zachary A.

doi:10.7554/elife.55909.sa2

Cited by 4 publications

(5 citation statements)

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“…For example, POMC neurons in ARC have shown elevated autophagy, an independent marker of neuronal stress or injury, in mice fed HFD for 8 months ( Thaler et al, 2012 ). In other hypothalamic regions, signs of neuronal injury, including long-lasting desensitization of neurons and a reduction in synaptic inputs, have also been observed in DIO ( Beutler et al, 2020 ; Moraes et al, 2009 ). In response to chronic HFD, homeostatic circuits of neuronal activity are disrupted ( Beutler et al, 2020 ).…”

Section: Consequences Of Reactive Astrocytesmentioning

confidence: 99%

“…In other hypothalamic regions, signs of neuronal injury, including long-lasting desensitization of neurons and a reduction in synaptic inputs, have also been observed in DIO ( Beutler et al, 2020 ; Moraes et al, 2009 ). In response to chronic HFD, homeostatic circuits of neuronal activity are disrupted ( Beutler et al, 2020 ). Moreover, chronic HFD impairs neuronal responses to nutrients and hormones in a way that is expected to promote weight gain, which lasts for weeks after mice have been returned to a low-fat diet and lost weight ( Beutler et al, 2020 ).…”

Section: Consequences Of Reactive Astrocytesmentioning

confidence: 99%

“…In response to chronic HFD, homeostatic circuits of neuronal activity are disrupted ( Beutler et al, 2020 ). Moreover, chronic HFD impairs neuronal responses to nutrients and hormones in a way that is expected to promote weight gain, which lasts for weeks after mice have been returned to a low-fat diet and lost weight ( Beutler et al, 2020 ).…”

Section: Consequences Of Reactive Astrocytesmentioning

confidence: 99%

“…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 ).…”

Section: Introductionmentioning

confidence: 99%

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Role of Hypothalamic Reactive Astrocytes in Diet-Induced Obesity

Park

Lee

2022

Molecules and Cells

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Hypothalamus is a brain region that controls food intake and energy expenditure while sensing signals that convey information about energy status. Within the hypothalamus, molecularly and functionally distinct neurons work in concert under physiological conditions. However, under pathological conditions such as in diet-induced obesity (DIO) model, these neurons show dysfunctional firing patterns and distorted regulation by neurotransmitters and neurohormones. Concurrently, resident glial cells including astrocytes dramatically transform into reactive states. In particular, it has been reported that reactive astrogliosis is observed in the hypothalamus, along with various neuroinflammatory signals. However, how the reactive astrocytes control and modulate DIO by influencing neighboring neurons is not well understood. Recently, new lines of evidence have emerged indicating that these reactive astrocytes directly contribute to the pathology of obesity by synthesizing and tonically releasing the major inhibitory transmitter GABA. The released GABA strongly inhibits the neighboring neurons that control energy expenditure. These surprising findings shed light on the interplay between reactive astrocytes and neighboring neurons in the hypothalamus. This review summarizes recent discoveries related to the functions of hypothalamic reactive astrocytes in obesity and raises new potential therapeutic targets against obesity.

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Section: Consequences Of Reactive Astrocytesmentioning

confidence: 99%

Section: Consequences Of Reactive Astrocytesmentioning

confidence: 99%

Section: Consequences Of Reactive Astrocytesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of Hypothalamic Reactive Astrocytes in Diet-Induced Obesity

Park

Lee

2022

Molecules and Cells

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“…When a mouse detects and/or consumes a food source, ARC AGRP neuronal activity drops proportionately to the perceived and actual energy content of the food, such that more caloric foods induce larger and longer-lasting inhibition of AGRP neuronal activity. [16][17][18]85 This activity then gradually recovers prior to triggering a subsequent feeding bout, and this cycle continues until enough calories have been consumed to meet current homeostatic need. In this light, chemogenetic inhibition of ARC AGRP neurons is likely either (1) not powerful enough to suppress ongoing ARC AGRP activity caused by 22-h food restriction or (2) incapable of reversing the effects triggered in downstream brain regions like the PVH to reduce initial feeding bouts.…”

Section: Articlementioning

confidence: 99%

Hypothalamic control of interoceptive hunger

et al. 2021

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Identification of an endocannabinoid gut-brain vagal mechanism controlling food reward and energy homeostasis

Berland

Castel

Montalban

et al. 2020

Preprint

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The regulation of food intake, a sine qua non requirement for survival, thoroughly shapes feeding and energy balance by integrating both homeostatic and hedonic values of food. Unfortunately, the widespread access to palatable food has led to the development of feeding habits that are independent from metabolic needs. Among these, binge eating (BE) is characterized by uncontrolled voracious eating. While reward deficit seems to be a major contributor of BE, the physiological and molecular underpinnings of BE establishment remain elusive. Here, we combined a physiologically relevant BE mouse model with multiscale in vivo integrative approaches to explore the functional connection between the gut-brain axis and the reward and homeostatic brain structures.Our results show that BE elicits compensatory adaptations requiring the gut-to-brain axis which, through the vagus nerve, relies on the permissive actions of peripheral endocannabinoids (eCBs) signaling. Selective inhibition of peripheral CB1 receptors resulted in a vagus-dependent increased hypothalamic activity, modified metabolic efficiency, and dampened activity of mesolimbic dopamine circuit, altogether leading to the suppression of palatable eating. We provide compelling evidence for a yet unappreciated physiological integrative mechanism by which variations of peripheral eCBs control the activity of the vagus nerve, thereby in turn gating the additive responses of both homeostatic and hedonic brain circuits which govern homeostatic and reward-driven feeding.In conclusion, we reveal that vagus-mediated eCBs/CB1R functions represent an interesting and innovative target to modulate energy balance and food-reward disorders.

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Author response: Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat

Cited by 4 publications

References 0 publications

Role of Hypothalamic Reactive Astrocytes in Diet-Induced Obesity

Role of Hypothalamic Reactive Astrocytes in Diet-Induced Obesity

Hypothalamic control of interoceptive hunger

Identification of an endocannabinoid gut-brain vagal mechanism controlling food reward and energy homeostasis

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