Epidemiological studies have shown that patterns of increased food intake and adiposity in overweight children are predictive of adult obesity, and thus lend urgency to the need for novel approaches to combat the """"""""obesity epidemic"""""""" in children. Research efforts in the past several decades have identified many signals and cellular components of neuronal circuits that regulate food intake and body weight;however, the vast majority of these studies have been performed in mature animals. Mild phenotypes resulting from disruptions of gene function or neuronal ablations from birth highlight the fact that neuronal circuits regulating energy homeostasis have an extraordinary compensatory capacity in young animals. A genetic model of hypothalamic leptin resistance (LeprHYP) provides a system to explore whether these """"""""compensatory"""""""" functions can be harnessed to improve metabolic phenotypes during a critical period of development for circuits regulating energy expenditure and adiposity. LeprHYP mice exhibit early-onset hyperphagia and obesity;however, they maintain stable levels of adiposity from 8 weeks of age. These findings support the idea that baselines for metabolic phenotypes that are established in young LeprHYP mice are defended with maturity. To explore whether altered metabolic parameters in young LeprHYP mice would be defended in adults, LeprHYP mice were pair-fed to the intake of controls from weaning through 10 weeks of age. Adiposity was reduced by ~20% during the pair- feeding, but more importantly, this lower level of adiposity was stably maintained throughout adulthood. These findings raised the possibility that the post-weaning period in rodents represents a critical period of development during which metabolic phenotypes develop in response to their nutrient/hormonal environment. The goal of the proposed studies is to define the temporal (Aim 1), physiological (Aim 2) and spatial (Aim 3) correlates of a putative """"""""critical period of development"""""""" for metabolic phenotypes. The time window of the sensitive period will be more precisely defined by reducing the duration of the pair-feeding (Aim 1, Exp. 1). To examine whether the molecular predicates of the putative critical period are similar to those that operate in sensory circuits, the ability of GABAA receptor agonists to prematurely initiate the onset of the critical period will be assessed (Aim 1, Exp. 2). Analyses in Aim 2 are designed to define the physiological adaptations associated with pair-feeding that persist in adults, as the circuits regulating these phenotypes likely represent an important source of plasticity in the system. Studies in Aim 3 will examine how hypothalamic leptin- sensing circuits interact with other neuronal circuits to regulate metabolic phenotypes. To examine interactions with hypothalamic insulin-sensing circuits, LeprHYP will be crossed to a floxed allele of insulin receptor (Insr) (Aim 3, Exp. 1). The contribution of extra-hypothalamic leptin-sensing neurons to either the reduction in adiposity achieved by pair-feeding and/or its maintenance in adults will be examined in mice with a pan- neuronal disruption of leptin signals (Aim 3, Exp 2).
Most studies of circuits in the brain that regulate feeding and body weight have been performed in adults. The proposed experiments are designed to identify the components of the circuits that are critical for establishing early patterns of percent body fat and metabolic rate in young animals, as they are likely to be more responsive to interventions at this time. This knowledge could lead to novel strategies to combat childhood obesity.
|Schwartz, Michael W; Seeley, Randy J; Zeltser, Lori M et al. (2017) Obesity Pathogenesis: An Endocrine Society Scientific Statement. Endocr Rev 38:267-296|
|Lerea, Jaclyn S; Ring, Laurence E; Hassouna, Rim et al. (2016) Reducing Adiposity in a Critical Developmental Window Has Lasting Benefits in Mice. Endocrinology 157:666-78|
|Juan De Solis, Alain; Baquero, Arian F; Bennett, Camdin M et al. (2016) Postnatal undernutrition delays a key step in the maturation of hypothalamic feeding circuits. Mol Metab 5:198-209|
|Chong, Angie C N; Vogt, Merly C; Hill, Alexis S et al. (2015) Central insulin signaling modulates hypothalamus-pituitary-adrenal axis responsiveness. Mol Metab 4:83-92|
|Zeltser, Lori M (2015) Developmental influences on circuits programming susceptibility to obesity. Front Neuroendocrinol 39:17-27|
|Chong, Angie C N; Greendyk, Richard A; Zeltser, Lori M (2015) Distinct networks of leptin- and insulin-sensing neurons regulate thermogenic responses to nutritional and cold challenges. Diabetes 64:137-46|
|Baquero, Arian F; de Solis, Alain J; Lindsley, Sarah R et al. (2014) Developmental switch of leptin signaling in arcuate nucleus neurons. J Neurosci 34:9982-94|
|Schwartz, Gary J; Zeltser, Lori M (2013) Functional organization of neuronal and humoral signals regulating feeding behavior. Annu Rev Nutr 33:1-21|
|Zeltser, Lori M; Seeley, Randy J; Tschöp, Matthias H (2012) Synaptic plasticity in neuronal circuits regulating energy balance. Nat Neurosci 15:1336-42|
|Ring, Laurence E; Zeltser, Lori M (2010) Disruption of hypothalamic leptin signaling in mice leads to early-onset obesity, but physiological adaptations in mature animals stabilize adiposity levels. J Clin Invest 120:2931-41|