Changes in energy expenditure and physical activity over 15 years of environmental changes: The Maycoba project.

OBJECTIVE: This work aimed to parse out the role of changing environments on body composition, total energy expenditure, and physical activity in the Mexican Pima, a population experiencing rapid industrialization. METHODS: Using doubly labeled water, we compared energy expenditure and physical activity in a longitudinal cohort of Mexican Pima (n = 26; female: 12) in 1995 and 2010. Body mass and composition were assessed by bioimpedance analysis. To determine the effects of environmental factors on body weight independent of age, we compared the 1995 longitudinal cohort with an age- and sex-matched cross-sectional cohort (n = 26) in 2010. RESULTS: Body mass, fat mass, and fat-free mass all significantly increased between 1995 and 2010. Despite a 13% average increase in body weight, weight-adjusted total daily energy expenditure decreased significantly. Measured physical activity levels also decreased between 1995 and 2010, after we adjusted for weight. CONCLUSIONS: Our results suggest that the recent industrialization of the Maycoba region in Sonora, Mexico, has contributed to a decrease in physical activity, in turn contributing to weight gain and metabolic disease among the Mexican Pima.

Effects of ketone bodies on energy expenditure, substrate utilization, and energy intake in humans.

The potential of ketogenic approaches to regulate energy balance has recently gained attention since ketones may influence both energy expenditure and energy intake. In this narrative review, we summarized the most relevant evidence about the role of ketosis on energy expenditure, substrate utilization, and energy intake in humans. We considered different strategies to induce ketosis, such as fasting, dietary manipulation, and exogenous ketone sources. In general, ketosis does not have a major influence on energy expenditure but promotes a shift in substrate utilization towards ketone body oxidation. The strategies to induce ketosis by reduction of dietary carbohydrate availability (e.g., ketogenic diets) do not independently influence energy intake, being thus equally effective for weight loss as diets with higher carbohydrate content. In contrast, the intake of medium-chain triglycerides and ketone esters induces ketosis and appears to increase energy expenditure and reduce energy intake in the context of high carbohydrate availability. These latter strategies lead to slightly enhanced weight loss. Unfortunately, distinguishing the effects of the various ketogenic strategies per se from the effects of other physiological responses is not possible with the available human data. Highly controlled, inpatient studies using targeted strategies to isolate the independent effects of ketones are required to adequately address this knowledge gap.

Contribution of brown adipose tissue to human energy metabolism.

The present "obesogenic' environment has favored excessive energy intake resulting in the current obesity epidemic and its associated diseases. The epidemic has incentivized scientists to develop novel behavioral and pharmacological strategies that enhance energy expenditure to compensate for excessive energy intake. Although physical activity is effective to increase total energy expenditure, it is insufficient to induce negative energy balance and weight loss. With the discovery of brown adipose tissue (BAT) in adult humans, BAT activation soon emerged as a potential strategy for elevating energy expenditure. BAT is the only tissue that expresses uncoupling protein 1, conferring on this tissue high thermogenic capacity due to a low efficiency for mitochondrial ATP generation. Potential manipulation of BAT mass and activity has fueled the interest in altering whole-body energy balance through increased energy expenditure. Remarkable advances have been made in quantifying the amount and activity of BAT in humans. Many studies have concluded that the amount of active BAT appears insufficient to induce meaningful increases in energy expenditure. Thus, the majority of studies report that BAT activation does not influence body weight and metabolic control in humans. Strategies to increase BAT mass and/or to potentiate BAT activity seem necessary.

Metabolic flexibility to lipid availability during exercise is enhanced in individuals with high insulin sensitivity.

Metabolic flexibility to lipid (MetFlex-lip) is the capacity to adapt lipid oxidation to lipid availability. Hypothetically, impaired MetFlex-lip in skeletal muscle induces accumulation of lipid metabolites that interfere with insulin signaling. Our aim was to compare MetFlex-lip during exercise in subjects with low (Low_IS) vs. high (High_IS) insulin sensitivity. Twenty healthy men were designated as Low_IS or High_IS on the basis of the median of the homeostatic model assessment of insulin resistance index. Groups had similar age, body mass index, and maximum oxygen uptake (V̇o2max). Subjects cycled at 50% V̇o2max until expending 650 kcal. Adaptation in lipid oxidation was calculated as the drop in respiratory quotient (RQ) at the end of exercise vs. the maximum RQ (ΔRQ). Lipid availability was calculated as the increase in circulating nonesterified fatty acids (NEFA) at the end of exercise vs. the minimum NEFA (ΔNEFA). ΔRQ as a function of ΔNEFA was used to determine MetFlex-lip. On average, RQ and circulating NEFA changed similarly in both groups. However, ΔRQ correlated with ΔNEFA in High_IS ( r = -0.83, P < 0.01) but not in Low_IS ( r = -0.25, P = 0.48) subjects. Thus the slope of the ΔRQ vs. ΔNEFA relationship was steeper in High_IS vs. Low_IS subjects (-0.139 ± 0.03 vs. -0.025 ± 0.03 RQ·mmol-1·l-1, respectively; P < 0.05), with similar intercepts. We conclude that in subjects with High_IS lipid-to-carbohydrate oxidation ratio adapts to the increased circulating NEFA availability during exercise. Such MetFlex-lip appears impaired in subjects with Low_IS. Whether a cause-effect relationship exists between impaired MetFlex-lip and low insulin sensitivity remains to be determined.

Analysis of type 2 diabetes and obesity genetic variants in Mexican Pima Indians: Marked allelic differentiation among Amerindians at HLA.

Prevalence of diabetes and obesity in Mexican Pima Indians is low, while prevalence in US Pima Indians is high. Although lifestyle likely accounts for much of the difference, the role of genetic factors is not well explored. To examine this, we genotyped 359 single nucleotide polymorphisms, including established type 2 diabetes and obesity variants from genome-wide association studies (GWAS) and 96 random markers, in 342 Mexican Pimas. A multimarker risk score of obesity variants was associated with body mass index (BMI; ß = 0.81 kg/m2 per SD, P = 0.0066). The mean value of the score was lower in Mexican Pimas than in US Pimas (P = 4.3 × 10-11 ), and differences in allele frequencies at established loci could account for approximately 7% of the population difference in BMI; however, the difference in risk scores was consistent with evolutionary neutrality given genetic distance. To identify loci potentially under recent natural selection, allele frequencies at 283 variants were compared between US and Mexican Pimas, accounting for genetic distance. The largest differences were seen at HLA markers (e.g., rs9271720, difference = 0.75, P = 8.7 × 10-9 ); genetic distances at HLA were greater than at random markers (P = 1.6 × 10-46 ). Analyses of GWAS data in 937 US Pimas also showed sharing of alleles identical by descent at HLA that exceeds its genomic expectation (P = 7.0 × 10-10 ). These results suggest that, in addition to the widely recognized balancing selection at HLA, recent directional selection may also occur, resulting in marked allelic differentiation between closely related populations.

Myokine Expression in Muscle and Myotubes in Response to Exercise Stimulation.

PURPOSE: Myokines have been shown to affect muscle physiology and exert systemic effects. We endeavored to investigate a panel of myokine mRNA expression after a single exercise bout (studies 1 and 2) to measure myokine mRNA in primary human myotubes in an in vitro exercise model (study 2). METHODS: Vastus lateralis muscle biopsies were obtained from 20 healthy males (age, 24.0 ± 4.5 yr; BMI, 23.6 ± 1.8 kg·m)(-2) before and after a single exercise bout (650 kcal at 50% V˙O2max). Primary myotubes from active and sedentary male donors were treated with a pharmacological cocktail (palmitate, forskolin, and ionomycin (PFI)) to mimic exercise-stimulated contractions in vitro. RESULTS: Interleukin 6 and 8 (IL-6 and IL-8), leukocyte-inducing factor, and connective tissue growth factor (CTGF) mRNA levels increased approximately 10-fold after a single exercise bout (all P < 0.001), whereas myostatin levels decreased (P < 0.05). Key correlations between myokine expression and parameters of muscle and whole-body physiology were found: myostatin versus skeletal muscle citrate synthase activity (r = -0.69, P < 0.001), V˙O2max (r = -0.64, P = 0.002) and the percentage of Type I fibers (r = -0.55, P = 0.01); IL-6 versus the RER (r = 0.45, P = 0.04), homeostatic model assessment of insulin resistance (r = 0.44, P = 0.05), and serum lactate (r = 0.50, P = 0.02). Myokine expressions in myotubes from sedentary donors for CTGF and myostatin decreased, whereas IL-6 and IL-8 increased after PFI treatment. In myotubes from active donors, myokine expression increased for IL-6, CTGF, and myostatin but decreased for IL-8 after PFI treatment. CONCLUSION: These data offer insight into the differences in regulation of myokine expression and their possible physiologic relationships.

Environmentally Driven Increases in Type 2 Diabetes and Obesity in Pima Indians and Non-Pimas in Mexico Over a 15-Year Period: The Maycoba Project.

OBJECTIVE: The global epidemics of type 2 diabetes and obesity have been attributed to the interaction between lifestyle changes and genetic predisposition to these diseases. We compared the prevalences of type 2 diabetes and obesity in Mexican Pima Indians, presumed to have a high genetic predisposition to these diseases, to those in their non-Pima neighbors, both of whom over a 15-year period experienced a transition from a traditional to a more modern lifestyle. RESEARCH DESIGN AND METHODS: Prevalence of diabetes, impaired fasting glucose, impaired glucose tolerance, and obesity in Mexican Pimas (n = 359) and non-Pima Mexicans (n = 251) were determined in 2010 using methods identical to those used in 1995. RESULTS: During this 15-year period, age-adjusted diabetes prevalence was unchanged in Pima men (5.8% in 1995 vs. 6.1% in 2010) yet increased in non-Pima men from 0.0 to 8.6% (P < 0.05). Diabetes prevalence tended to increase in both Pima women (9.4 vs. 13.4%) and non-Pima women (4.8 vs. 9.5%). Age-adjusted prevalence of obesity increased significantly in all groups (6.6 vs. 15.7% in Pima men; 8.5 vs. 20.5% in non-Pima men; 18.9. vs 36.3% in Pima women; 29.5 vs. 42.9% in non-Pima women). CONCLUSIONS: Type 2 diabetes prevalence increased between 1995 and 2010 in non-Pima men, and to a lesser degree in women of both groups, but it did not increase in Pima men. Prevalence of obesity increased among Pimas and non-Pimas of both sexes. These changes occurred concomitantly with an environmental transition from a traditional to a more modernized lifestyle.

Study design of the Maycoba Project: obesity and diabetes in Mexican Pimas.

OBJECTIVE: To focus on the rationale and methods of the Maycoba Project. METHODS: Study population included Mexican Pima Indians (MPI) and Blancos aged ≥20-years, living in the village of Maycoba and surrounding area. Surveys in 1995 and 2010 included a medical history, biochemical and anthropomet- ric measurements. Additionally, socio- economic, physical activity, and dietary interviews were conducted. The 2010 study incorporated investigations on type 2 diabetes (T2D) and obesity-associated genetic alleles and human-envi- ronment changes. RESULTS: The study results are limited to demographic data and description of the eligible and ex- amined sample. CONCLUSIONS: This study may yield important information on T2D and obesity etiology in a traditional population exposed to environmental changes.

Adipose tissue expression of adipose (WDTC1) gene is associated with lower fat mass and enhanced insulin sensitivity in humans.

OBJECTIVE: The overexpression of the adipose gene (adp/WDTC1) in mice inhibits lipid accumulation and improves the metabolic profile. Subcutaneous fat adp expression in humans and its relation to metabolic parameters was evaluated. DESIGN AND METHODS: Abdominal subcutaneous fat adp expression, insulin sensitivity (clamp), and respiratory quotient (RQ; indirect calorimetry) were assessed in: 36 obese and 56 BMI-, race-, and sex-matched type 2 diabetic volunteers (Look AHEAD Adipose Ancillary Study); 37 nondiabetic Pima Indians including obese (n = 18) and nonobese (n = 19) subjects and; 62 nonobese nondiabetic subjects at the Pennington Center in the ADAPT study. RESULTS: In the Look AHEAD Study, adp expression normalized for cyclophilin B was higher in males versus females (1.27 ± 0.06 vs. 1.11 ± 0.04; P < 0.01) but not after controlling for body fat. Adp expression was not influenced by the presence of diabetes but was related to body fat (r = -0.23; P = 0.03), insulin sensitivity (r = 0.23; P = 0.03) and fasting/insulin-stimulated RQ (r = 0.31 and 0.33; P < 0.01). In Pima Indians, adp expression was also higher in males versus females (1.00 ± 0.05 vs. 0.77 ± 0.05; P = 0.02) and higher in nonobese versus obese (1.02 ± 0.05 vs. 0.80 ± 0.06; P = 0.03). In the ADAPT study, there was no difference in adp expression between males and females. CONCLUSION: Consistent with animal studies, our results suggest that high adp expression in human adipose tissue is associated with lower adiposity and enhanced glucose utilization.

Role of skeletal muscle mitochondrial density on exercise-stimulated lipid oxidation.

Reduced skeletal muscle mitochondrial density is proposed to lead to impaired muscle lipid oxidation and increased lipid accumulation in sedentary individuals. We assessed exercise-stimulated lipid oxidation by imposing a prolonged moderate-intensity exercise in men with variable skeletal muscle mitochondrial density as measured by citrate synthase (CS) activity. After a 2-day isoenergetic high-fat diet, lipid oxidation was measured before and during exercise (650 kcal at 50% VO(2)max) in 20 healthy men with either high (HI-CS = 24 ± 1; mean ± s.e.) or low (LO-CS = 17 ± 1 nmol/min/mg protein) muscle CS activity. Vastus lateralis muscle biopsies were obtained before and immediately after exercise. Respiratory exchange data and blood samples were collected at rest and throughout the exercise. HI-CS subjects had higher VO(2)max (50 ± 1 vs. 44 ± 2 ml/kg fat free mass/min; P = 0.01), lower fasting respiratory quotient (RQ) (0.81 ± 0.01 vs. 0.85 ± 0.01; P = 0.04) and higher ex vivo muscle palmitate oxidation (866 ± 168 vs. 482 ± 78 nmol/h/mg muscle; P = 0.05) compared to LO-CS individuals. However, whole-body exercise-stimulated lipid oxidation (20 ± 2 g vs. 19 ± 1 g; P = 0.65) and plasma glucose, lactate, insulin, and catecholamine responses were similar between the two groups. In conclusion, in response to the same energy demand during a moderate prolonged exercise bout, reliance on lipid oxidation was similar in individuals with high and low skeletal muscle mitochondrial density. This data suggests that decreased muscle mitochondrial density may not necessarily impair reliance on lipid oxidation over the course of the day since it was normal under a high-lipid oxidative demand condition. Twenty-four-hour lipid oxidation and its relationship with mitochondrial density need to be assessed.

Dietary adherence to long-term controlled feeding in a calorie-restriction study in overweight men and women.

BACKGROUND: The success of clinical dietary interventions depends on the motivation and willingness of study participants to adhere to the prescribed or provided diet. The aim of this study was to assess participants' adherence to their provided diet over the 6-month duration of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE). METHODS: Investigators assessed the dietary adherence of 46 men and women who completed the first phase of the CALERIE trial. Volunteers were randomized to 1 of 4 dietary intervention groups: control, calorie restriction, calorie restriction with exercise, and low-calorie diet. Participants were provided with foods during 2 weeks of baseline and during the first 12 weeks and the last 2 weeks of the intervention as outpatients, and they completed a daily self-report form to assess diet adherence. The data are expressed as mean ± standard deviation or standard error of the mean. Pearson's correlation coefficient was determined to examine the relationship between assigned energy levels and total energy intake. RESULTS: Deviations reported were for eating nonstudy foods as well as not eating study foods. There were few deviations, and when converted to mean calories per day these did not affect total energy (weeks -3 to 2 = 10.25 ± 4.82, weeks 1-4 = 9.93 ± 12.52, weeks 5-11 = 8.38 ± 7.42, weeks 22-23 = 0.53 ± 3.97 kcal/d). The associations between assigned energy level and actual intake were high for all groups (P = .001), weeks -3 to -2 (r = 0.999), weeks 1-4 (r = 0.998), weeks 5-11 (r = 0.999), and weeks 22-23 (r = 0.998). CONCLUSIONS: The data provide evidence that dietary adherence is good when all foods are provided and when participants are highly motivated.

Differences in insulin resistance in Mexican and U.S. Pima Indians with normal glucose tolerance.

CONTEXT: Insulin resistance is a major risk factor for the development of type 2 diabetes in Pima Indians, a population with the highest prevalence of type 2 diabetes mellitus in the world. Their Mexican counterpart, living a traditional lifestyle in the mountains of Sonora, have at least 5 times less diabetes than the U.S. Pima Indians. OBJECTIVE: We evaluated whether Mexican Pima Indians had lower insulin resistance than U.S. Pima Indians. DESIGN AND PATIENTS: We compared fasting insulin and homeostasis model assessment for insulin resistance (HOMA-IR) in 194 Mexican Pima Indians (100 females, 94 males) and 449 U.S. Pima Indians (246 females, 203 males) with normal glucose tolerance from a cross-sectional study. Adjusted differences of log-transformed outcomes (fasting insulin and HOMA-IR) between groups were evaluated using multiple linear regression models and paired t test in a matched subset. RESULTS: Unadjusted fasting insulin and HOMA-IR were much lower in the Mexican Pima Indians than in their U.S. counterparts. After adjusting by obesity, age, and sex, mean (95% confidence interval) for fasting insulin was 6.22 (5.34-7.24) vs. 13.56 µU/ml (12.27-14.97) and for HOMA-IR 1.40 (1.20-1.64) vs. 3.07 (2.77-3.40), respectively, for Mexican Pima and U.S. Pima Indians. Results were confirmed in subset matched for age, sex, and body fat. CONCLUSION: Our results indicate that Mexican Pima Indians have lower insulin resistance in comparison with their genetically related U.S. counterparts, even after controlling for differences in obesity, age, and sex. This finding underscores the importance of lifestyle factors as protecting factors against insulin resistance in individuals with a high propensity to develop diabetes.

Effects of traditional and western environments on prevalence of type 2 diabetes in Pima Indians in Mexico and the U.S.

OBJECTIVE: Type 2 diabetes and obesity have genetic and environmental determinants. We studied the effects of different environments on these diseases in Pima Indians in Mexico and the U.S. RESEARCH DESIGN AND METHODS: Adult Pima-Indian and non-Pima populations in the Sierra Madre mountains of Mexico were examined using oral glucose tolerance tests and assessments for obesity, physical activity, and other risk factors. Results were compared with those from Pima Indians in Arizona. Both Pima populations were typed for DNA polymorphisms to establish their genetic similarity. RESULTS: The age- and sex-adjusted prevalence of type 2 diabetes in the Mexican Pima Indians (6.9%) was less than one-fifth that in the U.S. Pima Indians (38%) and similar to that of non-Pima Mexicans (2.6%). The prevalence of obesity was similar in the Mexican Pima Indians (7% in men and 20% in women) and non-Pima Mexicans (9% in men and 27% in women) but was much lower than in the U.S. Pima Indians. Levels of physical activity were much higher in both Mexican groups than in the U.S. Pima Indians. The two Pima groups share considerable genetic similarity relative to other Native Americans. CONCLUSIONS: The much lower prevalence of type 2 diabetes and obesity in the Pima Indians in Mexico than in the U.S. indicates that even in populations genetically prone to these conditions, their development is determined mostly by environmental circumstances, thereby suggesting that type 2 diabetes is largely preventable. This study provides compelling evidence that changes in lifestyle associated with Westernization play a major role in the global epidemic of type 2 diabetes.

Impact of lifestyle on prevalence of kidney disease in Pima Indians in Mexico and the United States.

Pima Indians in the United States and Mexico share a common genetic background but have very different lifestyles. Comparisons were made of the frequency of obesity, diabetes, hypertension, and kidney disease in these geographically separated but susceptible populations. Mexican Pimas had higher levels of physical activity, less obesity, and a lower prevalence of diabetes than their US Pima counterparts. Mean blood pressure rose with worsening glucose tolerance, and the prevalence of elevated urinary albumin excretion was higher in patients with diabetes than in those without, regardless of whether they lived in the United States or Mexico. These findings illustrate the importance of lifestyle in the development of diabetes and in the subsequent occurrence of diabetic kidney disease.

Obesidad esencial en un ambiente obesigénico / Essential obesity in an obese environment

La obesidad y sus complicaciones médicas hacen necesario conocer sobre su fisiopatología y alentar nuevas estrategias de prevención en salud pública dirigidas a la sociedad en conjunto. Uno de los aspectos más importantes a tener en cuenta es el del ambiente obesigénico, favorable para ganar peso, junto a otros factores que desarrollan la obesidad

Obesidad esencial en un ambiente obesigénico / Essential obesity in an obese environment

La obesidad y sus complicaciones médicas hacen necesario conocer sobre su fisiopatología y alentar nuevas estrategias de prevención en salud pública dirigidas a la sociedad en conjunto. Uno de los aspectos más importantes a tener en cuenta es el del ambiente obesigénico, favorable para ganar peso, junto a otros factores que desarrollan la obesidad