CRFR1 in AgRP Neurons Modulates Sympathetic Nervous System Activity to Adapt to Cold Stress and Fasting

Kuperman, Yael; Weiss, Martin; Dine, Julien; Staikin, Katy; Golani, Ofra; Ramot, Assaf; Nahum, Tali; Kühne, Claudia; Shemesh, Yair; Wurst, Wolfgang; Harmelin, Alon; Deussing, Jan M.; Eder, Matthias; Chen, Alon

doi:10.1016/j.cmet.2016.04.017

Cited by 54 publications

(59 citation statements)

References 92 publications

(109 reference statements)

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“…Although the integrated neural circuit responsible for the effect of CR on lipolysis and fat utilization remains unknown, it presumably involves impaired sympathetic nervous system-mediated communication with peripheral tissues as seen in previous studies on AgRP function (6,16,17,36). Furthermore, an AgRP-.PVN pathway subpopulation is required to drive positive reinforcement after food intake in caloric-depleted mice (37,38).…”

Section: Discussionmentioning

confidence: 94%

Carnitine acetyltransferase (Crat) in hunger‐sensing AgRP neurons permits adaptation to calorie restriction

et al. 2018

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Hunger-sensing agouti-related peptide (AgRP) neurons ensure survival by adapting metabolism and behavior to low caloric environments. This adaption is accomplished by consolidating food intake, suppressing energy expenditure, and maximizing fat storage (nutrient partitioning) for energy preservation. The intracellular mechanisms responsible are unknown. Here we report that AgRP carnitine acetyltransferase (Crat) knockout (KO) mice exhibited increased fatty acid utilization and greater fat loss after 9 d of calorie restriction (CR). No differences were seen in mice with ad libitum food intake. Eleven days ad libitum feeding after CR resulted in greater food intake, rebound weight gain, and adiposity in AgRP Crat KO mice compared with wild-type controls, as KO mice act to restore pre-CR fat mass. Collectively, this study highlights the importance of Crat in AgRP neurons to regulate nutrient partitioning and fat mass during chronically reduced caloric intake. The increased food intake, body weight gain, and adiposity in KO mice after CR also highlights the detrimental and persistent metabolic consequence of impaired substrate utilization associated with CR. This finding may have significant implications for postdieting weight management in patients with metabolic diseases.-Reichenbach, A., Stark, R., Mequinion, M., Lockie, S. H., Lemus, M. B., Mynatt, R. L., Luquet, S., Andrews, Z. B. Carnitine acetyltransferase (Crat) in hunger-sensing AgRP neurons permits adaptation to calorie restriction.

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Section: Discussionmentioning

confidence: 94%

Carnitine acetyltransferase (Crat) in hunger‐sensing AgRP neurons permits adaptation to calorie restriction

et al. 2018

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“…Although the role of CRH in obesity is very complex, studies demonstrate that the CRH system has anorectic and thermogenic roles (Kuperman et al, 2016).…”

Section: Age and Diet Modulate The Expression Of The Corticotropin-rementioning

confidence: 99%

Early maturational emergence of adult-like emotional reactivity and anxiety after brief exposure to an obesogenic diet

Vega-Torres

Azadian

Rios-Orsini

et al. 2020

Preprint

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Background: Emerging evidence demonstrates that diet-induced obesity disrupts corticolimbic circuits underlying emotional regulation. Studies directed at understanding how obesity alters brain and behavior are easily confounded by a myriad of complications related to obesity. This study investigated the early neurobiological stress response triggered by an obesogenic diet. Furthermore, this study directly determined the combined impact of a short-term obesogenic diet and adolescence on critical behavioral and molecular substrates implicated in emotion regulation and stress.Methods: Adolescent (postnatal day 31) or adult (postnatal day 81) Lewis rats were fed for one week with an experimental Western-like high-saturated fat diet (WD, 41% kcal from fat) or a matched control diet (CD, 13% kcal from fat). We used the acoustic fear-potentiated startle (FPS) paradigm to determine the effects of the WD on cued fear conditioning and fear extinction. We used c-Fos mapping to determine the functional influence of the diet and stress on corticolimbic circuits. Results:We report that one-week WD consumption was sufficient to induce fear extinction deficits in adolescent rats, but not in adult rats. We identify fear-induced alterations in corticolimbic neuronal activation and demonstrate increased prefrontal cortex CRHR1 mRNA levels in the rats that consumed the WD. Conclusions:Our findings demonstrate that short-term consumption of an obesogenic diet during adolescence heightens behavioral and molecular vulnerabilities associated with risk for anxiety and stress-related disorders. Given that fear extinction promotes resilience, and that fear extinction principles are the Vega-Torres et. al., 3 foundation of psychological treatments for PTSD, understanding how obesogenic environments interact with the adolescent period to affect the acquisition and expression of fear extinction memories is of tremendous clinical relevance. KEYWORDS PTSD, diet-induced obesity, adolescence, anxiety, fear-potentiated startle, CRHR1 HIGHLIGHTS • Short-term WD consumption during adolescence impairs cued fear extinction memory retention in a fear-potentiated startle paradigm.• Short-term WD consumption during adolescence attenuates neuronal activation to electric footshock stress in the basomedial nuclei of the amygdala.• Short-term WD consumption increases CRHR1 mRNA levels in the medial prefrontal cortex.• Adult LEW rats exhibit increased basal HPA axis tone and heightened emotional reactivity to footshock stress relative to adolescent rats.

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“…AgRP itself is an endogenous melanocortin receptor antagonist and plays a role in peripheral nutrient partitioning during energy deficit (Joly-Amado et al, 2012; Wang et al, 2014; Warne et al, 2013). AgRP neurons are also important for ghrelin- and corticotropin-induced hepatic glucose output during fasting (Kuperman et al, 2016; Wang et al, 2014). We have previously shown that fasting enhances activation of NPY/AgRP-GI neurons by low glucose (Murphy et al, 2009b).…”

Section: Discussionmentioning

confidence: 99%

“…Sepsis and LPS reduce PEPCK expression leading to decreased hepatic glucose output (Feingold et al, 2012; McCallum et al, 1983). A growing literature suggests a role for NPY/AgRP neurons in triggering hepatic gluconeogenesis and restoring blood glucose after fasting (Könner et al, 2007; Kuperman et al, 2016; Wang et al, 2014). We hypothesize that activation of the NPY/AgRP-GI subpopulation in low glucose mediates this effect.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, activation of ARC Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons during energy deficit increases food intake and decreases energy expenditure (Aponte et al, 2011; Krashes et al, 2011; Stanley et al, 1986; White and Kershaw, 1990). NPY/AgRP neurons are also important for increased hepatic glucose output during fasting (Kuperman et al, 2016; Wang et al, 2014). Approximately 40% of ARC NPY/AgRP neurons are glucose-inhibited (GI) neurons.…”

Section: Introductionmentioning

confidence: 99%

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Lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα) blunt the response of Neuropeptide Y/Agouti-related peptide (NPY/AgRP) glucose inhibited (GI) neurons to decreased glucose

et al. 2016

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A population of Neuropeptide Y (NPY) neurons which co-express Agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus (ARC) are inhibited at physiological levels of brain glucose and activated when glucose levels decline (e.g. glucose-inhibited or GI neurons). Fasting enhances the activation of NPY/AgRP-GI neurons by low glucose. In the present study we tested the hypothesis that lipopolysaccharide (LPS) inhibits the enhanced activation of NPY/AgRP-GI neurons by low glucose following a fast. Mice which express green fluorescent protein (GFP) on their NPY promoter were used to identify NPY/AgRP neurons. Fasting for 24 hours and LPS injection decreased blood glucose levels. As we have found previously, fasting increased c-fos expression in NPY/AgRP neurons and increased the activation of NPY/AgRP-GI neurons by decreased glucose. As we predicted, LPS blunted these effects of fasting at the 24 hour time point. Moreover, the inflammatory cytokine tumor necrosis factor alpha (TNFα) blocked the activation of NPY/AgRP-GI neurons by decreased glucose. These data suggest that LPS and TNFα may alter glucose and energy homeostasis, in part, due to changes in the glucose sensitivity of NPY/AgRP neurons. Interestingly, our findings also suggest that NPY/AgRP-GI neurons use a distinct mechanism to sense changes in extracellular glucose as compared to our previous studies of GI neurons in the adjacent ventromedial hypothalamic nucleus.

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CRFR1 in AgRP Neurons Modulates Sympathetic Nervous System Activity to Adapt to Cold Stress and Fasting

Cited by 54 publications

References 92 publications

Carnitine acetyltransferase (Crat) in hunger‐sensing AgRP neurons permits adaptation to calorie restriction

Carnitine acetyltransferase (Crat) in hunger‐sensing AgRP neurons permits adaptation to calorie restriction

Early maturational emergence of adult-like emotional reactivity and anxiety after brief exposure to an obesogenic diet

Lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα) blunt the response of Neuropeptide Y/Agouti-related peptide (NPY/AgRP) glucose inhibited (GI) neurons to decreased glucose

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