Tirzepatide in PWS, HO and GNSO

Inclusion Criteria:

• Individuals 18-26 years with a BMI in the obesity range (BMI ≥95th percentile forage and sex or ≥30 kg/m2) with either 1) genetically confirmed diagnosis of PWS, 2)hypothalamic obesity as defined by damage to the medial hypothalamic regionresulting in dysregulation of satiety and energy balance as diagnosed by aphysician, 3) general obesity unrelated to a genetic syndrome or underlying medicalcondition

• In a stable care setting at least 6 months prior to enrollment

• Able and willing to participate in study visits including tolerating blood draws,urine samples and tolerate DXA scan.

• Ability to take weekly subcutaneous tirzepatide

• Consistent caregiver if they are not independent

• Stable diet and exercise regimen for at least 6 months prior to enrollment

• Able to use contraceptive methods if able to conceive offspring in order to preventunintentional pregnancy during the study

Exclusion Criteria:

• Current or recent (within 3 months of start of study drug initiation) use of weightloss medications

• Current use of insulin or sulfonylurea or other medication affecting insulinsecretion or GLP1 clearance

• Current or prior use of any GLP1A or DPP4 inhibitor during the 6 months beforescreening

• Any medications that may affect the study endpoints

• Significant weight change (>3% weight gain or loss) in the last 2 months prior toenrollment

• Change in dose of chronic endocrine medications (testosterone, estrogen,levothyroxine, or growth hormone medications) >10%/kg/day for at least 3 monthsprior to study

• Current pregnancy or desire to become pregnant within study period, currentlactation

• History of recurrent pancreatitis, CKD, gastroparesis

• Chronic/acute heart, kidney, or liver disease

• Personal or family history of medullary thyroid carcinoma or MEN syndrome type 2

• Uncontrolled diabetes (A1C >8.5%)

• DVT

• Cancer within the previous 5 years

• Current participation in an interventional clinical study

• Previous or planned surgical treatment for obesity

• Individuals with current substance abuse equivalnt to moderate or severe based onDSM 5 criteria (Hasin DS, 2013)

• Any suicidal ideation in the past year

• Unable to perform any of the procedures for the study

• Have a body weight, height, and/or width that that prohibits the ability to obtainaccurate measurements according to the DXA manufacturer's specification

• Any condition that would prevent successful participation in the study.