Gut–brain circuits for fat preference

Li, Meng-Tong; Tan, Hwei-Ee; Lu, Zhengyuan; Tsang, Katherine; Chung, Ashley J.; Zuker, Charles S.

doi:10.1038/s41586-022-05266-z

Cited by 58 publications

(61 citation statements)

References 64 publications

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“…In accordance, we found that SucrW 12Wk feeding increased AgRP neuronal activity and caloric intake without significantly altering bodyweight or body composition. These changes in neuronal firing mirror HFDinduced changes to AgRP neuronal firing rate in DIO mice [24,31], though to a lesser extent, likely driven by functional differences in fat-and sugar-sensitive afferents to the hypothalamus and AgRP neurons [33][34][35]77] or even disparate circuitries for hedonic and nutritional sugar preference [40]. Interestingly, fasting failed to further increase the F AP of AgRP neurons suggesting that (1) AgRP neurons are refractory to additional relevant stimuli, or (2) this rate represents a ceiling beyond which AgRP neurons are not able to sustain action potential firing.…”

Section: Discussionmentioning

confidence: 84%

“…Similarly, we and others have recently described acute and long-term synaptic mechanisms [31] that mediate AgRP neuronal hyperactivity ex vivo [24,28] and postprandial desensitization identified by in vivo calcium imaging studies [29,30]. While recent studies have identified distinct gut-brain pathways for fat and sugar signaling to AgRP/NPY neurons [33][34][35] the longterm influence of high dietary sucrose consumption on AgRP neuronal function, plasticity, and body weight has not been explored.…”

Section: Introductionmentioning

confidence: 99%

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High sucrose consumption decouples intrinsic and synaptic excitability of AgRP neurons without altering body weight

et al. 2023

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Background/Objective As the obesity epidemic continues, the understanding of macronutrient influence on central nervous system function is critical for understanding diet-induced obesity and potential therapeutics, particularly in light of the increased sugar content in processed foods. Previous research showed mixed effects of sucrose feeding on body weight gain but has yet to reveal insight into the impact of sucrose on hypothalamic functioning. Here, we explore the impact of liquid sucrose feeding for 12 weeks on body weight, body composition, caloric intake, and hypothalamic AgRP neuronal function and synaptic plasticity. Methods Patch-clamp electrophysiology of hypothalamic AgRP neurons, metabolic phenotyping and food intake were performed on C57BL/6J mice. Results While mice given sugar-sweetened water do not gain significant weight, they do show subtle differences in body composition and caloric intake. When given sugar-sweetened water, mice show similar alterations to AgRP neuronal excitability as in high-fat diet obese models. Increased sugar consumption also primes mice for increased caloric intake and weight gain when given access to a HFD. Conclusions Our results show that elevated sucrose consumption increased activity of AgRP neurons and altered synaptic excitability. This may contribute to obesity in mice and humans with access to more palatable (HFD) diets.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

High sucrose consumption decouples intrinsic and synaptic excitability of AgRP neurons without altering body weight

et al. 2023

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show abstract

“…In accordance, we found that SucrW 12Wk feeding increased AgRP neuronal activity and caloric intake without signi cantly altering bodyweight or body composition. These changes in neuronal ring mirror HFD-induced changes to AgRP neuronal ring rate in DIO mice [25,29], though to a lesser extent, likely driven by functional differences in fat-and sugar-sensitive afferents to the hypothalamus and AgRP neurons [33][34][35]63] or even disparate circuitries for hedonic and nutritional sugar preference [40]. Additionally, synaptic plasticity of excitatory and inhibitory inputs to AgRP neurons in lean SucrW 12Wk mice were akin to DIO HFD 8Wk fed mice [29].…”

Section: Discussionmentioning

confidence: 93%

“…Similarly, we and others have recently described acute and long-term synaptic mechanisms [29] that mediate AgRP neuronal hyperactivity ex vivo [25,28] and postprandial desensitization identi ed by in vivo calcium imaging studies [30,31]. While recent studies have identi ed distinct gut-brain pathways for fat and sugar signaling to AgRP/NPY neurons [33][34][35] the long-term in uence of high dietary sucrose consumption on AgRP neuronal function, plasticity, and body weight has not been explored.…”

Section: Introductionmentioning

confidence: 99%

High Sucrose consumption decouples intrinsic and synaptic excitability of AgRP neurons without altering body weight

Korgan

Oliveira-Abreu²,

Wei

et al. 2022

Preprint

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As the obesity epidemic continues, the understanding of macronutrient influence on central nervous system function is critical for understanding diet-induced obesity and potential therapeutics, particularly in light of the increased sugar content in processed foods. Previous research showed mixed effects of sucrose feeding on body weight gain but has yet to reveal insight into the impact of sucrose on hypothalamic functioning. Here, we explore the impact of liquid sucrose feeding for 12 weeks on body weight, body composition, caloric intake, and hypothalamic AgRP neuronal function and synaptic plasticity. While mice given sugar-sweetened water do not gain significant weight, they do show subtle differences in body composition and caloric intake. When given sugar-sweetened water, mice show similar alterations to AgRP neuronal excitability as in high-fat diet obese models. Increased sugar consumption also primes mice for increased caloric intake and weight gain when given access to a HFD. Our results show that elevated sucrose consumption increased activity of AgRP neurons and altered synaptic excitability. This may contribute to obesity in mice and humans with access to more palatable (HFD) diets.

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“…These cells have polarity and chemoreceptors on luminal side detect specific class of nutrients and cause secretion of peptides on the basolateral side ( Gutierrez-Aguilar and Woods, 2011 ). By using knockout animals and functional imaging of the nodose ganglion, Li et al proved preference of sugar and fat ingestion is controlled by gut-brain axis via intestinal stimulation of receptors on gut epithelium and vagal nerve transmission, in which SGLT-1 controls sugar preference while GPR40/GPR120 are the essential mediators of intestinal fat signals to the vagal neurons ( Li et al, 2022 ). Distribution of glucose sensors on enteroendocrine L-cells and the molecular mechanism involved in the regulation of GLP-1 secretion are well understood.…”

Section: Location Of Gpr40 Protein On Enteroendocrine L-cells—luminal...mentioning

confidence: 99%

Learn from failures and stay hopeful to GPR40, a GPCR target with robust efficacy, for therapy of metabolic disorders

Guan¹,

Xiong²

2022

Front. Pharmacol.

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GPR40 is a class A G-protein coupled receptor (GPCR) mainly expressed in pancreas, intestine, and brain. Its endogenous ligand is long-chain fatty acids, which activate GPR40 after meal ingestion to induce secretion of incretins in the gut, including GLP-1, GIP, and PYY, the latter control appetite and glucose metabolism. For its involvement in satiety regulation and metabolic homeostasis, partial and AgoPAM (Positive Allosteric Modulation agonist) GPR40 agonists had been developed for type 2 diabetes (T2D) by many pharmaceutical companies. The proof-of-concept of GPR40 for control of hyperglycemia was achieved by clinical trials of partial GPR40 agonist, TAK-875, demonstrating a robust decrease in HbA1c (-1.12%) after chronic treatment in T2D. The development of TAK-875, however, was terminated due to liver toxicity in 2.7% patients with more than 3-fold increase of ALT in phase II and III clinical trials. Different mechanisms had since been proposed to explain the drug-induced liver injury, including acyl glucuronidation, inhibition of mitochondrial respiration and hepatobiliary transporters, ROS generation, etc. In addition, activation of GPR40 by AgoPAM agonists in pancreas was also linked to β-cell damage in rats. Notwithstanding the multiple safety concerns on the development of small-molecule GPR40 agonists for T2D, some partial and AgoPAM GPR40 agonists are still under clinical development. Here we review the most recent progress of GPR40 agonists development and the possible mechanisms of the side effects in different organs, and discuss the possibility of developing novel strategies that retain the robust efficacy of GPR40 agonists for metabolic disorders while avoid toxicities caused by off-target and on-target mechanisms.

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Gut–brain circuits for fat preference

Cited by 58 publications

References 64 publications

High sucrose consumption decouples intrinsic and synaptic excitability of AgRP neurons without altering body weight

High sucrose consumption decouples intrinsic and synaptic excitability of AgRP neurons without altering body weight

High Sucrose consumption decouples intrinsic and synaptic excitability of AgRP neurons without altering body weight

Learn from failures and stay hopeful to GPR40, a GPCR target with robust efficacy, for therapy of metabolic disorders

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