Abstract
During development, prenatal and postnatal factors program homeostatic set points to regulate food intake and body weight in the adult. Combinations of genetic and environmental factors contribute to the development of neural circuitry that regulates whole-body energy homeostasis. Brain-derived neurotrophic factor (Bdnf) and its receptor, Tyrosine kinase receptor B (TrkB), are strong candidates for mediating the reshaping of hypothalamic neural circuitry, given their well-characterized role in the central regulation of feeding and body weight. Here, we employ a chemical-genetic approach using the TrkBF616A/F616A knock-in mouse model to define the critical developmental period in which TrkB inhibition contributes to increased adult fat mass. Surprisingly, transient TrkB inhibition in embryos, preweaning pups, and adults all resulted in long-lasting increases in body weight and fat content. Moreover, sex-specific differences in the effects of TrkB inhibition on both body weight and hypothalamic gene expression were observed at multiple developmental stages. Our results highlight both the importance of the Bdnf/TrkB pathway in maintaining normal body weight throughout life and the role of sex-specific differences in the organization of hypothalamic neural circuitry that regulates body weight.
Highlights
Neuropeptides and other secreted proteins expressed in the hypothalamus play a critical role in modulating body weight and food intake in adult animals [1,2]
The hypothalamus contains two populations of neurons—orexigenic [expressing agouti related protein (Agrp), and neuropeptide Y (Npy)] and anorexigenic [expressing pro-opiomelanocortin (Pomc) and cocaine- and amphetamine-regulated transcript (Cart)] neurons—that make up the central melanocortinergic system to modulate energy balance [3,4]
Dietary cues act in a critical period during prenatal and early postnatal development to regulate homeostatic set points that modulate food intake and body weight in the adult, a process known as metabolic imprinting [2]
Summary
Neuropeptides and other secreted proteins expressed in the hypothalamus play a critical role in modulating body weight and food intake in adult animals [1,2]. Hypothalamic energy balance is modulated by first-order neurons of the hypothalamus. The hypothalamus contains two populations of neurons—orexigenic [expressing agouti related protein (Agrp), and neuropeptide Y (Npy)] and anorexigenic [expressing pro-opiomelanocortin (Pomc) and cocaine- and amphetamine-regulated transcript (Cart)] neurons—that make up the central melanocortinergic system to modulate energy balance [3,4]. Dietary cues act in a critical period during prenatal and early postnatal development to regulate homeostatic set points that modulate food intake and body weight in the adult, a process known as metabolic imprinting [2]. Male rats that are undernourished in utero have reduced body weight as young adults, while females exhibit increased body weight [7]
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