Document text
Principal Investigator: Peter Nikolaevich Kalugin
Organization: HARVARD MEDICAL SCHOOL
Fiscal Year: 2024
Award: $53,974
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary
The central goal of this proposal is to elucidate how leptin transport into the cerebrospinal fluid (CSF)
and brain is gated at the choroid plexus (ChP), how such gating influences the action of leptin on reward-
related dopaminergic neurons, and how saturated ChP transport may contribute to leptin resistance in
obesity. Regulation of energy expenditure and feeding are crucial to an animal’s ability to survive and maintain
physiological homeostasis. Leptin is an endocrine factor secreted by adipocytes that participates in the regulation
of food intake and body weight. Acting on receptors in the brain, leptin exerts an overall effect to decrease
feeding, increase energy expenditure, and promote a lean phenotype. Leptin must enter the brain to reach its
receptors. In obesity, circulating leptin levels are elevated, but the ratio of CSF to serum leptin is reduced, and
leptin suppresses food intake when administered centrally but not peripherally. This suggests insufficient
transport of leptin into the CSF as a potential contributor to the development of obesity. Preliminary work has
implicated transcytosis through the blood-cerebrospinal fluid barrier of the ChP epithelium as a critical pathway
of leptin entry into the brain. In fact, local deletion of endocytic receptor low density lipoprotein receptor-related
protein 1 (LRP1) in the ChP epithelium impairs feeding suppression by peripheral leptin while keeping intact the
decrease in food intake in response to centrally delivered leptin. However, the real time dynamics of this
proposed transcytotic transport at the ChP are poorly understood. I propose to apply novel in vivo imaging
techniques to study leptin transcytosis through the ChP epithelium as well as its access to and effects
on leptin-sensitive dopaminergic circuitry in the ventral tegmental area (VTA) in real time in awake,
behaving mice. In Aim 1, I will refine recently developed tools to visualize leptin transcytosis at the ChP in real
time (see preliminary data) and quantitatively assess the effects of LRP1 deletion or overexpression on leptin
transport from the blood into the CSF. Once it reaches the brain, leptin is known to engage a number of neural
circuits. Dopaminergic neurons in the VTA encode the motivational salience of food and are normally inhibited
by leptin, leading to reduced motivation for food consumption. In obesity, however, dysregulated VTA
dopaminergic activity promotes compulsive eating. In Aim 2, I will extend the imaging toolkit to track the access
of leptin to the VTA parenchyma in parallel with recording the activity of individual VTA dopaminergic neurons,
and rigorously assess the interplay between leptin transcytosis at the ChP and the VTA dopaminergic responses
to palatable food in lean and obese mice. Additionally, I will confirm if LRP1 overexpression in the ChP epithelium
could be protective against the development of obesity. These studies will provide novel insights into the
pathways and mechanisms of leptin entry into the brain, assess the dynamics and downstream effects of leptin
signaling with unprecedented precision, and propose new therapeutic approaches for obesity and other
metabolic disorders.
Terms: <2-photon><21+ years old><Acute><Adipocytes><Adipose Cell><Adipose tissue><Adult><Adult Human><Animals><Apical><Apo E Receptor><ApoE Receptor><Apolipoprotein E Receptor><Area><Autoregulation><Binge Eating><Blood><Blood - brain barrier anatomy><Blood Plasma><Blood Reticuloendothelial System><Blood Serum><Blood capillaries><Blood-Brain Barrier><Body Weight><Brain><Brain Nervous System><CNS Nervous System><Calcium><Cell Communication and Signaling><Cell Signaling><Central Nervous System><Cerebrospinal Fluid><Choroid Plexus><Choroid Plexus Epithelium><Critical Paths><Critical Pathways><Cues><DA Neuron><DNA Therapy><Data><Disease><Disorder><Dopamine><Dopamine neuron><Eating><Encephalon><Endocrine><Endocrine Gland Secretion><Endothelium><Energy Expenditure><Energy Metabolism><Epithelial Cells><Epithelium><Exhibits><Fasting><Fat Cells><Fats><Fatty Tissue><Fatty acid glycerol esters><Feeding behaviors><Food><Food Intake><Food Intake Regulation><Gene Transfer Clinical><Genetic Intervention><Genetic Polymorphism><Goals><Hemato-Encephalic Barrier><High Fat Diet><Homeostasis><Hormones><Human><Hydroxytyramine><Image><Imaging Procedures><Imaging Technics><Imaging Techniques><Impairment><Individual><Infusion><Infusion procedures><Ingestive Behavior><Insulin Resistance><Intracellular Communication and Signaling><Knock-out><Knockout><LDL Receptors><LDL-Receptor Related Protein 1><Label><Leanness><Leptin><Leptin resistance><Lipocytes><Lipoprotein LDL Receptors><Lipoprotein Receptor><Liquid substance><Low Density Lipoprotein Receptor><Low Density Lipoprotein Receptor-Related Protein><Low-Density-Lipoprotein Receptor-Related Protein-1><Mature Lipocyte><Mature fat cell><Measures><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Methods><Mice><Mice Mammals><Modern Man><Molecular><Motivation><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurocyte><Neuroendocrine><Neuroendocrine System><Neurons><Neurosecretory Systems><Ob Gene Product><Ob Protein><Obese Gene Product><Obese Mice><Obese Protein><Obesity><Pathway interactions><Peripheral><Phenotype><Physiological Homeostasis><Plasma><Plasma Serum><Prediabetes><Prediabetes syndrome><Prediabetic State><Process><Proteins><Receptor Protein><Regulation><Reticuloendothelial System, Serum, Plasma><Rewards><Role><Satiation><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Structure of choroid plexus><Surface><Testing><Therapeutic Hormone><Thesaurismosis><Thinness><Time><Tropism><Ventral Tegmental Area><Viral Vector><Visualization><Wild Type Mouse><Work><adipose><adiposity><adulthood><alpha-2-Macroglobulin Receptor><alpha2-Macroglobulin Signaling Receptor><awake><biological signal transduction><blood cerebrospinal fluid barrier><bloodbrain barrier><calcium indicator><capillary><cerebral spinal fluid><compulsive eating><compulsive feeding><compulsive overeating><corpulence><design><designing><dopaminergic neuron><experiment><experimental research><experimental study><experiments><fasted><fasts><feeding><feeding-related behaviors><fluid><food consumption><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genomic therapy><glucose tolerance><imaging><imaging in vivo><in vivo><in vivo imaging><infusions><insight><insulin resistant><insulin tolerance><liquid><median eminence><metabolism disorder><monolayer><neural><neural circuit><neural circuitry><neurocircuitry><neuronal><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><nutrient intake activity><ob/ob mouse><obesity development><obesity intervention><obesity therapy><obesity treatment><overexpress><overexpression><pathway><polymorphism><pre-diabetes><pre-diabetic><prediabetic><receptor><response><satiety><social role><spinal fluid><synaptic circuit><synaptic circuitry><tool><transcytosis><two-photon><ventral tegmentum><white adipose tissue><wildtype mouse><yellow adipose tissue>