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Lateral Hypothalamic Area Neurotensin Neurons Are Required for Control of Orexin Neurons and Energy Balance.

ABSTRACT: The lateral hypothalamic area (LHA) is essential for motivated ingestive and locomotor behaviors that impact body weight, yet it remains unclear how the neurochemically defined subpopulations of LHA neurons contribute to energy balance. In particular, the role of the large population of LHA neurotensin (Nts) neurons has remained ambiguous due to the lack of methods to easily visualize and modulate these neurons. Because LHA Nts neurons are activated by leptin and other anorectic cues and they modulate dopamine or local LHA orexin neurons implicated in energy balance, they may have important, unappreciated roles for coordinating behaviors necessary for proper body weight. In this study, we genetically ablated or chemogenetically inhibited LHA Nts neurons in adult mice to determine their necessity for control of motivated behaviors and body weight. Genetic ablation of LHA Nts neurons resulted in profoundly increased adiposity compared with mice with intact LHA Nts neurons, as well as diminished locomotor activity, energy expenditure, and water intake. Complete loss of LHA Nts neurons also led to downregulation of orexin, revealing important cross-talk between the LHA Nts and orexin populations in maintenance of behavior and body weight. In contrast, chemogenetic inhibition of intact LHA Nts neurons did not disrupt orexin expression, but it suppressed locomotor activity and the adaptive response to leptin. Taken together, these data reveal the necessity of LHA Nts neurons and their activation for controlling energy balance, and that LHA Nts neurons influence behavior and body weight via orexin-dependent and orexin-independent mechanisms.

SUBMITTER: Brown J

PROVIDER: S-EPMC6669822 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Lateral Hypothalamic Area Neurotensin Neurons Are Required for Control of Orexin Neurons and Energy Balance.

Brown Juliette J Sagante Andrew A Mayer Thomas T Wright Anna A Bugescu Raluca R Fuller Patrick M PM Leinninger Gina G

Endocrinology 20180901 9

The lateral hypothalamic area (LHA) is essential for motivated ingestive and locomotor behaviors that impact body weight, yet it remains unclear how the neurochemically defined subpopulations of LHA neurons contribute to energy balance. In particular, the role of the large population of LHA neurotensin (Nts) neurons has remained ambiguous due to the lack of methods to easily visualize and modulate these neurons. Because LHA Nts neurons are activated by leptin and other anorectic cues and they mo ...[more]

PMID: 30010830

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Project description:OBJECTIVE:The cocaine- and amphetamine-regulated transcript (CART) codes for a pivotal neuropeptide important in the control of appetite and energy homeostasis. However, limited understanding exists for the defined effector sites underlying CART function, as discrepant effects of central CART administration have been reported. METHODS:By combining Cart-cre knock-in mice with a Cart adeno-associated viral vector designed using the flip-excision switch (AAV-FLEX) technology, specific reintroduction or overexpression of CART selectively in CART neurons in the arcuate nucleus (Arc) and lateral hypothalamic area (LHA), respectively, was achieved. The effects on energy homeostasis control were investigated. RESULTS:Here we show that CART neuron-specific reintroduction of CART into the Arc and LHA leads to distinct effects on energy homeostasis control. Specifically, CART reintroduction into the Arc of otherwise CART-deficient Cartcre/cre mice markedly decreased fat mass and body weight, whereas CART reintroduction into the LHA caused significant fat mass gain and lean mass loss, but overall unaltered body weight. The reduced adiposity in ArcCART;Cartcre/cre mice was associated with an increase in both energy expenditure and physical activity, along with significantly decreased Npy mRNA levels in the Arc but with no change in food consumption. Distinctively, the elevated fat mass in LHACART;Cartcre/cre mice was accompanied by diminished insulin responsiveness and glucose tolerance, greater spontaneous food intake, and reduced energy expenditure, which is consistent with the observed decrease of brown adipose tissue temperature. This is also in line with significantly reduced tyrosine hydroxylase (Th) and notably increased corticotropin-releasing hormone (Crh) mRNA expressions in the paraventricular nucleus (PVN). CONCLUSIONS:Taken together, these results identify catabolic and anabolic effects of CART in the Arc and LHA, respectively, demonstrating for the first time the distinct and region-specific functions of CART in controlling feeding and energy homeostasis.

Dataset Information

Lateral Hypothalamic Area Neurotensin Neurons Are Required for Control of Orexin Neurons and Energy Balance.

Publications

Lateral Hypothalamic Area Neurotensin Neurons Are Required for Control of Orexin Neurons and Energy Balance.

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