Neurons in the brain detect changes in nutritional status and environment, and relay signals to their downstream targets to regulate food intake and energy expenditure, the balance of which is critical to maintain normal body weight and protect from obesity. Given the complexity of the brain, the neurobiological mechanisms underlying these processes are poorly understood. Efficient treatment of obesity is thus still lacking. Although a lot of success has been recently achieved in dissecting the neural circuitry of feeding behaviors, the research to understand the neural basis of energy expenditure is still in its infancy. In a recent study, we focused on a group of hypothalamic neurons labeled by cre activity in Rip-cre transgenic mice, thereafter referred to as RIP neurons, and uncovered an arcuate-based circuit that selectively drives brown adipose tissue (BAT) activity and energy expenditure. Specifically, we disrupted GABAergic neurotransmission from these neurons in a cre-dependent manner and observed that mice lacking synaptic GABA release from RIP neurons have reduced energy expenditure and become obese, and are extremely sensitive to high fat diet-induced obesity due to defective thermogenesis. Leptin's ability to stimulate energy expenditure is also attenuated in these animals. With pharmacogenetic DREADDs, we acutely and selectively activated the subset of RIP neurons in the arcuate nucleus (ARC) and rapidly stimulated BAT-mediated energy expenditure. Moreover, with channelrhodopsin-assisted circuit mapping (CRACM), we characterized that ARC RIP neurons project to the paraventricular nucleus (PVH) and specifically innervate the PVH neurons that project to the nucleus of solitary tract (NTS) in the brain stem. Of great interest, we observed that RIP neurons have no effects in regulating food intake. These findings demonstrate that GABAergic RIP neurons in the ARC selectively drive energy expenditure, contribute to leptin's stimulatory effect on thermogenesis, and protect against diet-induced obesity. Given the importance of these neurons in maintaining body weight and resisting obesity, it is crucial to comprehensively understand their related neural circuitry.
In Aim 1, we set out to employ advanced optogenetic and deep brain imaging approaches to investigate the regulations of RIP neurons during thermoregulation and functionally assess their projection to the PVH in stimulating energy expenditure.
In Aim 2, we will focus on the output signals of RIP neurons in the PVH and identify their efferent subset of neurons that convey their signals to the BAT. Finally, in Aim 3, we will survey the afferent inputs of RIP neurons within a microcircuit in the arcuate nucleus and scrutinize their functions in regulating energy expenditure. In total, these proposed studies could significantly advance our understanding of the neural basis of energy expenditure and provide novel information to prevent obesity.

Public Health Relevance

Neurons in the brain regulate the balance between calorie intake and energy expenditure, maintain normal body weight, and prevent the development of metabolic disorders like obesity. Due to the complexity of the brain and limited availability of technologies, the neural mechanisms underlying these processes are still poorly understood. In this proposal, we will employ multiple cutting-edge technologies to investigate a neural circuit in the brain that selectively drives energy expenditure and prevents diet-induced obesity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Hyde, James F
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Tufts University
Schools of Medicine
United States
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Lockie, Sarah H; Stark, Romana; Mequinion, Mathieu et al. (2018) Glucose Availability Predicts the Feeding Response to Ghrelin in Male Mice, an Effect Dependent on AMPK in AgRP Neurons. Endocrinology 159:3605-3614
Killion, Elizabeth A; Reeves, Andrew R; El Azzouny, Mahmoud A et al. (2018) A role for long-chain acyl-CoA synthetase-4 (ACSL4) in diet-induced phospholipid remodeling and obesity-associated adipocyte dysfunction. Mol Metab 9:43-56
Xu, Jie; Bartolome, Christopher L; Low, Cho Shing et al. (2018) Genetic identification of leptin neural circuits in energy and glucose homeostases. Nature 556:505-509
Felsted, Jennifer A; Chien, Cheng-Hao; Wang, Dongqing et al. (2017) Alpha2delta-1 in SF1+ Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis. Cell Rep 21:2737-2747
Vetrivelan, Ramalingam; Kong, Dong; Ferrari, Loris L et al. (2016) Melanin-concentrating hormone neurons specifically promote rapid eye movement sleep in mice. Neuroscience 336:102-113
Kong, Dong; Dagon, Yossi; Campbell, John N et al. (2016) A Postsynaptic AMPK?p21-Activated Kinase Pathway Drives Fasting-Induced Synaptic Plasticity in AgRP Neurons. Neuron 91:25-33