Neuropeptide Y resists excess loss of fat by lipolysis in calorie-restricted mice: a trait potential for the life-extending effect of calorie restriction

Park, Seong Joon; Komatsu, Toshimitsu; Kim, Sang Eun; Tanaka, Katsuya; Hayashi, Hiroko; Mori, Ryoichi; Shimokawa, Isao

doi:10.1111/acel.12558

Cited by 19 publications

(24 citation statements)

References 46 publications

(57 reference statements)

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“…This shift toward fatty acid utilization might be facilitated by reduced AgRP-mediated antagonism of MC4R, resulting in augmented MC4R signaling and increased lipolysis (8,9). Nevertheless, our results are consistent with the ablation of AgRP or NPY neurons on substrate utilization and nutrient partitioning (4,10).…”

Section: Discussionsupporting

confidence: 78%

“…AgRP itself is an endogenous antagonist at the melanocortin 4 receptor (MC4R), and central AgRP antagonism of the MC4R increases BAT temperature and glucose oxidation as indicated by the respiratory exchange ratio (RER), whereas stimulating MC receptor signaling increases lipolysis (8,9). Moreover, NPY knockout (KO) mice have increased fat loss caused by lipolysis during calorie restriction (CR) (10). Collectively, these results show that both AgRP and NPY peptides conserve energy by regulating nutrient partitioning and utilization in peripheral tissues.…”

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confidence: 99%

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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: Discussionsupporting

confidence: 78%

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confidence: 99%

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

et al. 2018

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“…These diseases are caused by long-term energy metabolism disequilibrium, together with an imbalance between energy intake and energy expenditure. Studies have revealed that NPY is a major regulator in balancing energy metabolism [26, 94, 95] and resists excessive loss of fat by lipolysis in calorie-restricted mice indicating a trait potential for the life-extending effect of calorie restriction [95]. The NPY receptors, as is reported, can regulate energy balance and body weight in a cooperative manner.…”

Section: The Characteristics Of Human Npy Receptorsmentioning

confidence: 96%

A Promising Therapeutic Target for Metabolic Diseases: Neuropeptide Y Receptors in Humans

et al. 2017

Cell Physiol Biochem

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Human neuropeptide Y (hNPY) is one of the most widely expressed neurotransmitters in the human central and peripheral nervous systems. It consists of 36 highly conserved amino acid residues, and was first isolated from the porcine hypothalamus in 1982. While it is the most recently discovered member of the pancreatic polypeptide family (which includes neuropeptide Y, gut-derived hormone peptide YY, and pancreatic polypeptide), NPY is the most abundant peptide found in the mammalian brain. In order to exert particular functions, NPY needs to bind to the NPY receptor to activate specific signaling pathways. NPY receptors belong to the class A or rhodopsin-like G-protein coupled receptor (GPCR) family and signal via cell-surface receptors. By binding to GPCRs, NPY plays a crucial role in various biological processes, including cortical excitability, stress response, food intake, circadian rhythms, and cardiovascular function. Abnormal regulation of NPY is involved in the development of a wide range of diseases, including obesity, hypertension, atherosclerosis, epilepsy, metabolic disorders, and many cancers. Thus far, five receptors have been cloned from mammals (Y1, Y2, Y4, Y5, and y6), but only four of these (hY1, hY2, hY4, and hY5) are functional in humans. In this review, we summarize the structural characteristics of human NPY receptors and their role in metabolic diseases.

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“…In mice, for example, adipose loss due to calorie restriction occurs in a graded manner, mirroring that of lifespan extension (Mitchell et al., ). However, contradictory evidence suggests that fat loss under calorie restriction provided no benefit or was detrimental to lifespan (Chiba et al., ; Liao et al., ; Park et al., ). Thus, although body composition appears to play a role in mediating the effect of calorie restriction on lifespan, the exact nature of this relationship is currently unclear.…”

Section: Introductionmentioning

confidence: 99%

“…It is known that the body has a limited capacity for storing excess protein, with surplus nitrogen being excreted as urea (Delimaris, ; Heaney, ; Tarnopolsky et al., ). However, there is a positive relationship between fat intake and fat storage, with ingestion of high‐fat diets resulting in increased fat storage and obesity and thus potentially the associated negative consequences for health and survival (reviewed Hariri & Thibault, ; but see Liao et al., ; Chiba et al., ; Park et al., ). The protein leverage hypothesis suggests that individuals eat primarily to obtain a target protein level, with carbohydrate and fat being overconsumed on low‐protein diets in an attempt to reach this protein level (Huang et al., ; Simpson & Raubenheimer, ; Sørensen et al., ).…”

Section: Introductionmentioning

confidence: 99%

Body macronutrient composition is predicted by lipid and not protein content of the diet

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et al. 2017

Ecology and Evolution

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Diet is an important determinant of fitness‐related traits including growth, reproduction, and survival. Recent work has suggested that variation in protein:lipid ratio and particularly the amount of protein in the diet is a key nutritional parameter. However, the traits that mediate the link between dietary macronutrient ratio and fitness‐related traits are less well understood. An obvious candidate is body composition, given its well‐known link to health. Here, we investigate the relationship between dietary and body macronutrient composition using a first‐generation laboratory population of a freshwater fish, the three‐spine stickleback (Gasterosteus aculeatus). Carbohydrate is relatively unimportant in the diet of predatory fish, facilitating the exploration of how dietary protein‐to‐lipid ratio affects their relative deposition in the body. We find a significant effect of lipid intake, rather than protein, on body protein:lipid ratio. Importantly, this was not a result of absorbing macronutrients in relation to their relative abundance in the diet, as the carcass protein:lipid ratios differed from those of the diets, with ratios usually lower in the body than in the diet. This indicates that individuals can moderate their utilization, or uptake, of ingested macronutrients to reach a target balance within the body. We found no effect of diet on swimming endurance, activity, or testes size. However, there was an effect of weight on testes size, with larger males having larger testes. Our results provide evidence for the adjustment of body protein:lipid ratio away from that of the diet. As dietary lipid intake was the key determinant of body composition, we suggest this occurs via metabolism of excess protein, which conflicts with the predictions of the protein leverage hypothesis. These results could imply that the conversion and excretion of protein is one of the causes of the survival costs associated with high‐protein diets.

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Neuropeptide Y resists excess loss of fat by lipolysis in calorie-restricted mice: a trait potential for the life-extending effect of calorie restriction

Cited by 19 publications

References 46 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

A Promising Therapeutic Target for Metabolic Diseases: Neuropeptide Y Receptors in Humans

Body macronutrient composition is predicted by lipid and not protein content of the diet

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