Effect of Caloric Restriction on Fat Oxidation in Obese Men and Women (Magellan II)

• Change from baseline amount of fat oxidation at 14 days [ Time Frame: Days 0, 14 ] [ Designated as safety issue: No ]

  Measurements will be taken from Biopsy

  Expected Results

  • Overweight and obese subjects will show a wide variation in fat oxidation in response to the low calorie diet
  • Approximately one-third of study participants will not meet target weight loss by four weeks
  • Following an overnight fast (prior to and during LCD) individuals that fail to meet the target weight loss will be characterized by decreased whole body fat oxidation and increased carbohydrate oxidation (measured by indirect calorimetry)
• Change from baseline amount of fat oxidation at 1 week intervals [ Time Frame: Days 0, 7, 14, 28, 49, 56 ] [ Designated as safety issue: No ]

  Measurements will be taken from resting metabolic rate (RMR)

  Expected Results

  • Overweight and obese subjects will show a wide variation in fat oxidation in response to the low calorie diet
  • Approximately one-third of study participants will not meet target weight loss by four weeks
  • Following an overnight fast (prior to and during LCD) individuals that fail to meet the target weight loss will be charaterized by decreased whole body fat oxidation and increased carbohydrate oxidation (measured by indirect calorimetry)

• Change in area of hepatic lipid and skeletal muscle IMCL content [ Time Frame: Days -7, -1, 14, 56 ] [ Designated as safety issue: No ]

  Masured with magnetic resonance spectroscopy (MRS)

  Expected results

  • 1H-MRS can measure hepatic lipid and skeletal muscle (intramyocellular lipid) IMCL content with low test-retest variability
  • 1H-MRS can sensitively monitor reductions (or lack thereof) in skeletal muscle IMCL and liver intrahepatocellular lipid (IHCL) concentration during caloric restriction
  • Reductions in IMCL and IHCL will be higher in subjects with lower fasting respiratory quotients (RQ) at baseline/during LCD
• Frequency of presence of serum biomarkers at baseline [ Time Frame: Day 0 ] [ Designated as safety issue: No ]

  Expected results

  - One or more of the measured parameters will emerge as biomarkers of low fat oxidation

• Frequency of presence of serum biomarkers at 14 days [ Time Frame: Day 14 ] [ Designated as safety issue: No ]

  Expected results

  - One or more of the measured parameters will emerge as biomarkers of low fat oxidation

The purpose of this study is to better understand the different ways our bodies burn fat which may be important for obesity, diabetes, and cardiovascular disease.

In this study the investigators will examine the hypothesis that overweight/obese individuals that are unable to meet target weight loss goals on a low calorie diet (LCD) are intrinsically less metabolically flexible than their weight-losing counterparts. The investigators expect that this 'inflexibility' will be characterized by impaired fat oxidation (as determined by indirect calorimetry) in response to caloric restriction. If this were the case, these subjects may represent a population of 'super-responders' likely to demonstrate a robust response to approaches to increase fat oxidation. The investigators will also measure lipid concentrations in skeletal muscle and liver by hydrogen 1 magnetic resonance (1H-MRS) to determine both the stability of these measurements as well as the magnitude of changes that can be seen during LCD.

• Obesity
• Overweight
• Metabolic Diseases

• Behavioral: Low Calorie Diet (LCD)
  A Diet History Questionnaire will be completed, and the subjects will have dietary counseling and be provided shakes. The low calorie diet will begin, to continue for a period of 8 weeks.
• Drug: Phentermine

  Individuals not on track to achieve their target weight by four weeks will receive the drug Phentermine to promote weight loss. Then, following eight weeks LCD (or four weeks LCD + four weeks LCD+Phentermine), in the event that they did not achieve the target weight loss, subjects will be given the option to continue with the LCD + Phentermine for up to an additional 12 weeks, under a doctor's supervision.

  Protection Against Risk:

  • Prior to administering any phentermine, a history and physical including EKG will be conducted (at the screening visit) and will be used to determine whether the participant is clear to receive the medication.
  • Participants will see the study doctor or nurse practitioner at every study visit after the drug is initiated.

• Active Comparator: Overweight, no drug
  After screening, overweight (BMI 27.0 - 30.0, inclusive) subjects will be started on a low calorie diet (approximately 900-1000 kcal/d) until a target weight loss is achieved.
  Intervention: Behavioral: Low Calorie Diet (LCD)
• Active Comparator: Obese with no drug
  After screening, overweight (obese subjects (BMI ≥30 - ≤40.0) subjects (n=35) will be started on a low calorie diet (approximately 900-1000 kcal/d) until a target weight loss is achieved. Individuals not on track to achieve their target weight by four weeks will receive the drug Phentermine to promote weight loss. Then, following eight weeks LCD (or four weeks LCD + four weeks LCD+Phentermine), in the event that they did not achieve the target weight loss, subjects will be given the option to continue with the LCD + Phentermine for up to an additional 12 weeks, under a doctor's supervision.
  Intervention: Behavioral: Low Calorie Diet (LCD)
• Placebo Comparator: Overweight with Phentermine
  After screening, overweight (BMI 27.0 - 30.0, inclusive) subjects will be started on a low calorie diet (approximately 900-1000 kcal/d) until a target weight loss is achieved. Individuals not on track to achieve their target weight by four weeks will receive the drug Phentermine to promote weight loss. Then, following eight weeks LCD (or four weeks LCD + four weeks LCD+Phentermine), in the event that they did not achieve the target weight loss, subjects will be given the option to continue with the LCD + Phentermine for up to an additional 12 weeks, under a doctor's supervision.
  Interventions:

  • Behavioral: Low Calorie Diet (LCD)
  • Drug: Phentermine
• Placebo Comparator: Obese with Phentermine
  After screening, obese subjects (BMI ≥30 - ≤40.0) subjects (n=35) will be started on a low calorie diet (approximately 900-1000 kcal/d) until a target weight loss is achieved. Individuals not on track to achieve their target weight by four weeks will receive the drug Phentermine to promote weight loss. Then, following eight weeks LCD (or four weeks LCD + four weeks LCD+Phentermine), in the event that they did not achieve the target weight loss, subjects will be given the option to continue with the LCD + Phentermine for up to an additional 12 weeks, under a doctor's supervision.
  Interventions:

  • Behavioral: Low Calorie Diet (LCD)
  • Drug: Phentermine

• Holloway GP, Bonen A, Spriet LL. Regulation of skeletal muscle mitochondrial fatty acid metabolism in lean and obese individuals. Am J Clin Nutr. 2009 Jan;89(1):455S-62S. Epub 2008 Dec 3. Review.
• Simoneau JA, Kelley DE. Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in NIDDM. J Appl Physiol. 1997 Jul;83(1):166-71.
• Ukropcova B, Sereda O, de Jonge L, Bogacka I, Nguyen T, Xie H, Bray GA, Smith SR. Family history of diabetes links impaired substrate switching and reduced mitochondrial content in skeletal muscle. Diabetes. 2007 Mar;56(3):720-7. PubMed PMID: 17327442.
• Zurlo F, Lillioja S, Esposito-Del Puente A, Nyomba BL, Raz I, Saad MF, Swinburn BA, Knowler WC, Bogardus C, Ravussin E. Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ. Am J Physiol. 1990 Nov;259(5 Pt 1):E650-7.
• Koves TR, Ussher JR, Noland RC, Slentz D, Mosedale M, Ilkayeva O, Bain J, Stevens R, Dyck JR, Newgard CB, Lopaschuk GD, Muoio DM. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 2008 Jan;7(1):45-56.
• Salehzadeh F, Rune A, Osler M, Al-Khalili L. Testosterone or 17{beta}-estradiol exposure reveals sex-specific effects on glucose and lipid metabolism in human myotubes. J Endocrinol. 2011 Aug;210(2):219-29. Epub 2011 Jun 1.
• Hamadeh MJ, Devries MC, Tarnopolsky MA. Estrogen supplementation reduces whole body leucine and carbohydrate oxidation and increases lipid oxidation in men during endurance exercise. J Clin Endocrinol Metab. 2005 Jun;90(6):3592-9. Epub 2005 Mar 8.
• Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL, Roden M, Shulman GI. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia. 1999 Jan;42(1):113-6. Erratum in: Diabetologia 1999 Mar;42(3):386. Diabetologia 1999 Oct;42(10):1269.
• Franklin RM, Kanaley JA. Intramyocellular lipids: effect of age, obesity, and exercise. Phys Sportsmed. 2009 Apr;37(1):20-6. Review.
• Goodpaster BH, Kelley DE, Wing RR, Meier A, Thaete FL. Effects of weight loss on regional fat distribution and insulin sensitivity in obesity. Diabetes. 1999 Apr;48(4):839-47.
• Lara-Castro C, Newcomer BR, Rowell J, Wallace P, Shaughnessy SM, Munoz AJ, Shiflett AM, Rigsby DY, Lawrence JC, Bohning DE, Buchthal S, Garvey WT. Effects of short-term very low-calorie diet on intramyocellular lipid and insulin sensitivity in nondiabetic and type 2 diabetic subjects. Metabolism. 2008 Jan;57(1):1-8.
• Tamura Y, Tanaka Y, Sato F, Choi JB, Watada H, Niwa M, Kinoshita J, Ooka A, Kumashiro N, Igarashi Y, Kyogoku S, Maehara T, Kawasumi M, Hirose T, Kawamori R. Effects of diet and exercise on muscle and liver intracellular lipid contents and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2005 Jun;90(6):3191-6. Epub 2005 Mar 15.
• Mahmood S, Taketa K, Imai K, Kajihara Y, Imai S, Yokobayashi T, Yamamoto S, Sato M, Omori H, Manabe K. Association of fatty liver with increased ratio of visceral to subcutaneous adipose tissue in obese men. Acta Med Okayama. 1998 Aug;52(4):225-31.
• Lewis MC, Phillips ML, Slavotinek JP, Kow L, Thompson CH, Toouli J. Change in liver size and fat content after treatment with Optifast very low calorie diet. Obes Surg. 2006 Jun;16(6):697-701.
• Hall KD. Predicting metabolic adaptation, body weight change, and energy intake in humans. Am J Physiol Endocrinol Metab. 2010 Mar;298(3):E449-66. Epub 2009 Nov 24.
• Wells GD, Noseworthy MD, Hamilton J, Tarnopolski M, Tein I. Skeletal muscle metabolic dysfunction in obesity and metabolic syndrome. Can J Neurol Sci. 2008 Mar;35(1):31-40. Review. Erratum in: Can J Neurol Sci. 2008 Jul;35(3):402.
• Bergman RN, Ider YZ, Bowden CR, Cobelli C. Quantitative estimation of insulin sensitivity. Am J Physiol. 1979 Jun;236(6):E667-77.
• Elia M, Livesey G. Energy expenditure and fuel selection in biological systems: the theory and practice of calculations based on indirect calorimetry and tracer methods. World Rev Nutr Diet. 1992;70:68-131. Review.

Inclusion Criteria:

• Male or female subjects between the ages of 18 and 55 years, inclusive
• Body Mass Index (BMI) 27-30 kg/m2, inclusive, with hypertension, controlled (<140 / <90) either by diet or medication.
• BMI 30-40 kg/m2, inclusive.
• An informed consent document signed and dated by the subject or a legally acceptable representative.
• Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular (hypertension controlled (<140 / <90) either by diet or medication is acceptable), hepatic, psychiatric, neurologic, allergic, (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing), muscle disease, diabetes, or severe uncontrolled hypertension.
• Known hypersensitivity to phentermine, lidocaine, bupivicaine or any medication component of the study procedure.
• Presence of cardiac pacemaker, implanted cardiac defibrillator, or brain aneurysm clips.
• Any significant bleeding diathesis which could preclude recovery from the biopsy procedure. ASA, ibuprofen, and any other oral anti platelet agent will be discontinued at least 7 days prior to procedure.
• Abnormal CK as per site laboratory ranges.
• Subjects with either a medical history of or physical evidence of keloid scar formation upon physical examination.
• 12-lead electrocardiogram (ECG) demonstrating a clinically significant abnormality.
• Pregnant or nursing females or females less than 6 months postpartum from the scheduled date of collection.
• Participation in non-routine rigorous exercise (e.g., road races, heavy lifting, etc.) within one week prior to the muscle biopsy procedures.
• Presence of any condition in the investigator's opinion that may negatively affect subject safety or protocol adherence.
• Females of childbearing potential (any female except those with tubal ligation, hysterectomy, or absence of menses > 2years) unwilling to use an approved method of contraception (condom, diaphragm, implantable uterine device (IUD) that does not release hormones).
• Prior participation in the Magellan I study at the Translational Research Institute for Metabolism and Diabetes.