Project Grant R01DK139062

UNCOVERING THE ROLE OF HYPOTHALAMIC CILIARY CAMP SIGNALING IN SEX-SPECIFIC CONTROL OF METABOLIC HOMEOSTASIS - PROJECT SUMMARY / ABSTRACT DESPITE SIMILAR OBESITY RATES IN BOTH SEXES, THE UNDERLYING BIOLOGY OF EXCESSIVE WEIGHT GAIN IN WOMEN AND MEN IS BELIEVED TO DIFFER SIGNIFICANTLY. NEURONS IN THE VENTROMEDIAL NUCLEUS OF THE HYPOTHALAMUS (VMH) EXHIBIT SEXUALLY DIMORPHIC CHARACTERISTICS AND PLAY A CRUCIAL ROLE IN ENERGY BALANCE. HOWEVER, THE SIGNALING PATHWAYS WITHIN VMH NEURONS THAT CONTRIBUTE TO SEX-SPECIFIC CONTROL OF ENERGY BALANCE REMAIN LARGELY UNKNOWN. RECENTLY, THE PRIMARY CILIUM, A SOLITARY ANTENNA-LIKE SENSORY ORGANELLE FOUND IN MOST MAMMALIAN CELLS, INCLUDING NEURONS, HAS EMERGED AS A CRITICAL REGULATOR OF METABOLIC HOMEOSTASIS. HUMAN GENETIC STUDIES HAVE IDENTIFIED THE CILIA-SPECIFIC ADENYLATE CYCLASE 3 (ADCY3) AS A SIGNIFICANT OBESITY-RISK GENE AND ANIMAL STUDIES HAVE FURTHER SHOWN THAT GLOBAL ADCY3 KNOCKOUT MICE DEVELOP SEVERE OBESITY, PARTICULARLY IN FEMALES. HOWEVER, THE MECHANISM UNDERLYING ADCY3'S CONTRIBUTION TO FEMALE-BIASED WEIGHT GAIN REMAINS UNKNOWN. OUR RECENT FINDINGS INDICATE THAT SELECTIVE DELETION OF ADCY3 IN VMH NEURONS LEADS TO FEMALE-SPECIFIC OBESITY WITHOUT A SIGNIFICANT INCREASE IN FOOD INTAKE. ADCY3 IS ENRICHED IN ESTROGEN RECEPTOR ALPHA (ERA)- AND MELANOCORTIN 4 RECEPTOR (MC4R)-EXPRESSING NEURONS IN THE VENTROLATERAL SUBDIVISION OF VMH (VMHVL), WHICH ARE KNOWN TO AFFECT ENERGY EXPENDITURE (EE) IN FEMALE MICE. ADDITIONALLY, WE FOUND THAT ERA BINDS TO A PUTATIVE PROMOTER REGION OF THE ADCY3 GENE. BASED ON THESE COMPELLING PRELIMINARY OBSERVATIONS AND PREVIOUS LITERATURE SUGGESTING THAT MC4R, A GAS-COUPLED RECEPTOR ENRICHED IN PRIMARY CILIA, IS A DIRECT TRANSCRIPTIONAL TARGET OF ERA WITHIN VMHVL NEURONS AND INCREASES EE SPECIFICALLY IN FEMALE MICE, WE PROPOSE A NOVEL HYPOTHESIS THAT ADCY3 FUNCTIONS DOWNSTREAM OF ERA-DRIVEN MC4R SIGNALING AT THE PRIMARY CILIUM OF VMHVL NEURONS TO INCREASE EE IN FEMALES BY MODULATING THE EXCITABILITY AND/OR NEUROTRANSMISSION OF THESE NEURONS. THIS HYPOTHESIS WILL BE TESTED BY PURSUING FOLLOWING THREE AIMS: AIM-1) DETERMINE IF VMHVL ADCY3 IS NECESSARY FOR METABOLIC HOMEOSTASIS BY ACTING DOWNSTREAM OF ESTROGEN-ERA AND MC4R SIGNALING, AIM-2) DETERMINE IF INCREASING ADCY3 ACTIVITY IN VMHVL ERA+ NEURONS IS SUFFICIENT TO PROTECT AGAINST OBESITY, AND AIM-3) DETERMINE IF LOSS OF ADCY3 REDUCE THE EXCITABILITY AND/OR THE NEUROTRANSMITTER RELEASE OF VMHVL ERA+ NEURONS. THE PROPOSED RESEARCH AIMS TO SIGNIFICANTLY ADVANCE OUR UNDERSTANDING OF HYPOTHALAMIC SIGNALING PATHWAYS INVOLVED IN SEX-SPECIFIC REGULATION OF ENERGY HOMEOSTASIS. ADDITIONALLY, IT WILL PROVIDE NEW INSIGHTS INTO THE LARGELY UNKNOWN MECHANISMS BY WHICH CILIARY CAMP SIGNALING AFFECTS THE PHYSIOLOGY OF KEY HYPOTHALAMIC NEURONS THAT ARE CRUCIAL FOR METABOLIC HOMEOSTASIS. SUCH KNOWLEDGE MAY ULTIMATELY LEAD TO THE DEVELOPMENT OF A NOVEL STRATEGY TO EFFECTIVELY PREVENT OR TREAT OBESITY IN FEMALES.