The main purpose of this study is to examine the effect of prolonged (72 hour) administration of glucagon compared to placebo on energy expenditure in healthy, non-diabetic, obese subjects.

Inclusion Criteria:

• Age 18-55 years, inclusive.

• Body Mass Index (BMI) ≥27 to ≤45 kg/m2 and body weight <450 lbs.

• Stable body weight for 3 months (self-reported loss/gain <5%).

• Judged to be non-diabetic per the American Diabetes Association guidelines:

  1. fasting plasma glucose <126 mg/dL [7.0 mmol/L] and
  2. HbA1c <6.5% [48 mmol/mol]) and
  3. in good health on the basis of medical history, physical examination (PE), electrocardiogram (ECG), and normal laboratory values obtained from Screening visit labs.

• Understands the procedures and agrees to participate in the study program by giving written informed consent, and is willing to comply with the trial restrictions.

• Willing to avoid alcohol consumption for 48 hours prior to the inpatient study visit.

• Willing to avoid consumption of caffeine and caffeinated beverages for 24 hours prior to the inpatient study visit.

• Willing to avoid strenuous physical activity for 72 hours prior to the inpatient study visit.

Exclusion Criteria

• Treatment with any medication known to significantly impact body weight or energy metabolism (e.g., weight loss medications, atypical antipsychotics) within 3 months prior to screening except for stable physiological hormone replacement therapy (i.e., thyroid hormone, estrogen).

• Treatment with a selective serotonin reuptake inhibitor, a medication for depression or apomorphine within one week prior to screening due to interaction with Zofran.

• History of bariatric surgery.

• Current liver, renal, pulmonary, cardiac, oncologic, metabolic, gastrointestinal, or hematologic disease which the Investigator believes is clinically significant, including:

  a. Liver disease or liver injury as indicated by abnormal liver function tests (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, serum bilirubin) >3 × upper limit of normal (ULN), or history of hepatic cirrhosis.

• Impaired renal function as indicated by an estimated glomerular filtration rate (eGFR) <60 mL/min or urine albumin-to-creatinine ratio >35 mg/mmol.

• Significant cardiovascular disease, including Class III or greater congestive heart failure (CHF), coronary artery disease, second degree or greater heart block, or clinically significant arrhythmias; baseline second degree or greater heart block or prolonged QT syndrome (QTc interval ≥470 msec); or any major cardiovascular event within the last 3 years (including myocardial infarction [MI], transient ischemic attack, cerebrovascular accident [CVA], angina, and hospitalization due to CHF,transient ischemic attack, and CVA).

• Metabolic, or other endocrine disorders, including diagnosis of type 1 or type 2 diabetes mellitus [HbA1c ≥6.5%]), inadequately treated hyperthyroidism (thyroid stimulating hormone [TSH] below normal range) or hypothyroidism (TSH >ULN <10 U/mL and symptomatic or TSH >10 U/mL), Cushing's disease/syndrome, Addison's disease, hypogonadism, or genetic disorders linked to obesity.

• History of irritable bowel disease, recurrent nausea, or vomiting.

• Anemia (hemoglobin <12 g/dL in males, <11 g/dL in females).

• History of dyslipidemia: Fasting triglycerides (TG) >500 mg/dL and low-density lipoproteins (LDL) >250 mg/dL.

• Self-reported history of infection with hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV).

• History of recurrent sleep disturbances and/or prone to sleep disturbances based on lifestyle or employment (e.g., variable work schedule, overnight shift work, etc.).

• Diagnosis of sleep apnea with or without use of continuous positive airway pressure/BiPAP/AutoPAP.

• Major surgery within 3 months prior to screening.

• Blood donation within 4 weeks prior to screening.

• Participation in another investigational trial within 4 weeks prior to screening. The 4 week window will be derived from the date of the last trial medication and/or blood collection in a previous trial and/or adverse event (AE) related to trial drug screening of the current trial.

• Use of illicit drugs or nicotine-containing products within 3 months prior to screening.

• Poor intravenous (IV) access.

• Blood pressure <100/50 mmHg or ≥160/100 mmHg during screening.

• Heart rate ≥100 bpm during screening.

• Fasting plasma glucose <60 mg/dL or ≥126 mg/dL during screening.

• Female subjects who are, or intend to become, pregnant during the course of this study, are currently breastfeeding, or women of child-bearing potential (WOCBP) who refuse to use at least one method of birth control (oral contraceptives, intrauterine device, implanted or injectable contraceptives, abstinence).

• Translational Research Institute for Metabolism and Diabetes (TRI-MD) staff member or immediate relative of TRI-MD staff members directly involved

• History of any illness or condition that, in the opinion of the study investigator, might confound the results of the study or poses an additional risk to the subject by study participation.