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1.
Int J Obes (Lond) ; 44(10): 2149-2164, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32152498

RESUMO

BACKGROUND/OBJECTIVES: Maintaining energy balance is important to ensure a healthy organism. However, energy partitioning, coordinating the distribution of sufficient energy to different organs and tissues is equally important, but the control of this process is largely unknown. In obesity, an increase in fat mass necessitates the production of additional bone mass to cope with the increase in bodyweight and processes need to be in place to communicate this new weight bearing demand. Here, we investigate the interaction between leptin and NPY, two factors critically involved in the regulation of both energy metabolism and bone mass, in this process. METHODS: We assessed the co-localization of leptin receptors on NPY neurons using RNAScope followed by a systematic examination of body composition and energy metabolism profiling in male and female mice lacking leptin receptors specifically in NPY neurons (Leprlox/lox;NPYCre/+). The effect of short-term switching between chow and high-fat diet was also examined in these mice. RESULTS: We uncovered that leptin receptor expression is greater on a subpopulation of NPY neurons in the arcuate that do not express AgRP. We further show that Leprlox/lox;NPYCre/+ mice exhibit significantly increased adiposity while bone mass is diminished. These body composition changes occur in the absence of alterations in food intake or energy expenditure, demonstrating a prominent role for leptin signaling in NPY neurons in the control of energy partitioning. Importantly however, when fed a high-fat diet, these mice display a switch in energy partitioning whereby they exhibit a significantly enhanced ability to increase their bone mass to match the increased bodyweight caused by higher caloric intake concurrent with attenuated adiposity. CONCLUSIONS: Taken together, these results demonstrate that leptin signaling in NPY neurons is critical for coordinating energy partitioning between fat and bone mass especially during situations of changes in energy balance.


Assuntos
Tecido Adiposo/metabolismo , Osso e Ossos/metabolismo , Metabolismo Energético , Hipotálamo/metabolismo , Leptina/metabolismo , Neurônios/metabolismo , Adiposidade , Animais , Composição Corporal , Dieta Hiperlipídica , Ingestão de Energia , Feminino , Masculino , Camundongos , Receptores para Leptina
2.
Neuropeptides ; 80: 101994, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31740068

RESUMO

Neuropeptide Y (NPY) producing neurons in the arcuate nucleus (Arc) of the hypothalamus are essential to the regulation of food intake and energy homeostasis. Whilst they have classically been thought to co-express agouti-related peptide (AgRP), it is now clear that there is a sub-population of NPY neurons in the Arc that do not. Here, we show that a subset of AgRP-negative, NPY-positive neurons in the Arc also express neurotensin (NTS) and we use an NTS-Cre line to investigate the function of this sub-population of NPY neurons. The lack of NPY in NTS-positive neurons led to a marked reduction in fat mass and bodyweight as well as a significant reduction in food intake in male NPYlox/lox; NTScre/+ mice compared to controls. Despite the reduction in food intake, overall energy expenditure was similar between genotypes due to concomitant reduction in activity in NPYlox/lox; NTScre/+ mice. Furthermore, cortical bone mass was significantly reduced in NPYlox/lox;NTScre/+ mice with no evident alterations in the cancellous bone compartment, likely due to reduced leptin levels as a result of their reduced adiposity. Taken together, these data suggest that the sub-population of Arc NPY neurons expressing NTS are critical for regulating food intake, activity and fat mass but are not directly involved in the control of bone mass.


Assuntos
Peso Corporal/fisiologia , Metabolismo Energético/fisiologia , Neurônios/metabolismo , Neuropeptídeo Y/deficiência , Neurotensina/metabolismo , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Homeostase/fisiologia , Hipotálamo/metabolismo , Leptina/metabolismo , Camundongos Transgênicos , Neuropeptídeo Y/metabolismo , Fenótipo
4.
Cell Metab ; 30(1): 111-128.e6, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31031093

RESUMO

Neuropeptide Y (NPY) exerts a powerful orexigenic effect in the hypothalamus. However, extra-hypothalamic nuclei also produce NPY, but its influence on energy homeostasis is unclear. Here we uncover a previously unknown feeding stimulatory pathway that is activated under conditions of stress in combination with calorie-dense food; NPY neurons in the central amygdala are responsible for an exacerbated response to a combined stress and high-fat-diet intervention. Central amygdala NPY neuron-specific Npy overexpression mimics the obese phenotype seen in a combined stress and high-fat-diet model, which is prevented by the selective ablation of Npy. Using food intake and energy expenditure as readouts, we demonstrate that selective activation of central amygdala NPY neurons results in increased food intake and decreased energy expenditure. Mechanistically, it is the diminished insulin signaling capacity on central amygdala NPY neurons under combined stress and high-fat-diet conditions that leads to the exaggerated development of obesity.


Assuntos
Tonsila do Cerebelo/metabolismo , Hipotálamo/metabolismo , Neurônios/metabolismo , Neuropeptídeo Y/metabolismo , Obesidade/metabolismo , Animais , Temperatura Corporal , Dieta Hiperlipídica/efeitos adversos , Ingestão de Alimentos/fisiologia , Eletrofisiologia , Metabolismo Energético/fisiologia , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Insulina/metabolismo , Masculino , Camundongos , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real
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