Energy expenditure in the etiology of human obesity: spendthrift and thrifty metabolic phenotypes and energy-sensing mechanisms.

The pathogenesis of human obesity is the result of dysregulation of the reciprocal relationship between food intake and energy expenditure (EE), which influences daily energy balance and ultimately leads to weight gain. According to principles of energy homeostasis, a relatively lower EE in a setting of energy balance may lead to weight gain; however, results from different study groups are contradictory and indicate a complex interaction between EE and food intake which may differentially influence weight change in humans. Recently, studies evaluating the adaptive response of one component to perturbations of the other component of energy balance have revealed both the existence of differing metabolic phenotypes ("spendthrift" and "thrifty") resulting from overeating or underfeeding, as well as energy-sensing mechanisms linking EE to food intake, which might explain the propensity of an individual to weight gain. The purpose of this review is to debate the role that human EE plays on body weight regulation and to discuss the physiologic mechanisms linking EE and food intake. An increased understanding of the complex interplay between human metabolism and food consumption may provide insight into pathophysiologic mechanisms underlying weight gain, which may eventually lead to prevention and better treatment of human obesity.

Specific skeletal muscle sphingolipid compounds in energy expenditure regulation and weight gain in Native Americans of Southwestern heritage.

BACKGROUND/OBJECTIVES: In animal models, a role in the regulation of energy expenditure (EE) has been ascribed to sphingolipids, active components of cell membranes participating in cellular signaling. In humans, it is unknown whether sphingolipids have a role in the modulation of EE and, consequently, influence weight gain. The present study investigated the putative association of EE and weight gain with sphingolipid levels in the human skeletal muscle, a component of fat-free mass (the strongest determinant of EE), in adipose tissue and plasma. SUBJECTS/METHODS: Twenty-four-hour EE, sleeping metabolic rate (SMR) and resting metabolic rate (RMR) were assessed in 35 healthy Native Americans of Southwestern heritage (24 male; 30.2±7.73 years). Sphingolipid (ceramide, C; sphingomyelin, SM) concentrations were measured in skeletal muscle tissue, subcutaneous adipose tissue and plasma samples. After 6.68 years (0.26-12.4 years), follow-up weights were determined in 16 participants (4 females). RESULTS: Concentrations of C24:0, SM18:1/26:1 and SM18:0/24:1 in muscle were associated with 24-h EE (r=-0.47, P=0.01), SMR (r=-0.59, P=0.0008) and RMR (r=-0.44, P=0.01), respectively. Certain muscle sphingomyelins also predicted weight gain (for example, SM18:1/23:1, r=0.74, P=0.004). For specific muscle sphingomyelins that correlated with weight gain and EE (SM18:1/23:0, SM18:1/23:1 and SMR, r=-0.51, r=-0.41, respectively, all P<0.03; SM18:1/24:2 and RMR, r=-0.36, P=0.03), associations could be reproduced with SMR in adipose tissue (all r<-0.46, all P<0.04), though not in plasma. CONCLUSIONS: This study provides preliminary, novel evidence, that specific muscle and adipose tissue sphingolipid compounds are associated with EE and weight gain in Native Americans of Southwestern heritage. Further studies are warranted to investigate whether sphingolipids of different body compartments act in concert to modulate energy balance in humans.

Changes in glycemia, insulin and gut hormone responses to a slowly ingested solid low-carbohydrate mixed meal after laparoscopic gastric bypass or band surgery.

OBJECTIVE: To evaluate early changes in glycemia, insulin physiology and gut hormone responses to an easily tolerated and slowly ingested solid, low-carbohydrate mixed meal test (MMT) following laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB) surgery. SUBJECTS/METHODS: This was a prospective non-randomized study. Plasma glucose, insulin and c-peptide (to estimate hepatic insulin extraction; %HIE), incretins (GIP, aGLP-1) and pancreatic polypeptide (PP) responses to the MMT were measured at 4-8 weeks before and after surgery in obese, metabolically healthy patients (RYGB=10F or LAGB =7F/1M). Supplementary clamp data on basal endogenous glucose production (EGP) and peripheral insulin action (Rd=rate of glucose disposal) and metabolic clearance rates of insulin (MCR-INS) were available in five of the RYGB patients. Repeated measures were appropriately accounted for in the analyses. RESULTS: Following LAGB surgery, C-peptide and insulin MMT profiles (P=0.004 and P=0.0005, respectively) were lower with no change in %HIE (P=0.98). In contrast, in RYGB subjects, both fasting glucose and insulin (Δ=-0.66 mmol l-1, P⩽0.05 and Δ=-44.4 pmol l-1, P⩽0.05, respectively) decreased, and MMT glucose (P<0.0001) and insulin (P=0.001) but not c-peptide (P= 0.69) decreased. Estimated %HIE increased at fasting (Δ=8.4%, P⩽0.05) and during MMT (P=0.0005). Early (0-20 min) prandial glucose (0.27±0.26 versus 0.006±0.21 mmol l-1, P⩽0.05) and insulin (63(48, 66) versus 18(12, 24) pmol l-1, P⩽0.05) responses increased after RYGB. RYGB altered the trajectory of prandial aGLP-1 responses (treatment × trajectory P=0.02), and PP was lower (P<0.0001). Clamp data in a subset of RYGB patients showed early improvement in basal EGP (P=0.001), and MCR-INS (P=0.015). CONCLUSION: RYGB results in distinctly different changes in plasma glucose, insulin and gut hormone response patterns to a solid, slowly ingested low-carbohydrate MMT versus LAGB. Altered nutrient delivery, along with indirect evidence for changes in hepatic and peripheral insulin physiology, are consistent with the greater early improvement in glycemia observed after RYGB versus LAGB surgery.