Fasting glucagon-like peptide 1 concentration is associated with lower carbohydrate intake and increases with overeating

PURPOSE: Glucagon-like peptide 1 (GLP-1) is an incretin hormone that appears to play a major role in the control of food intake. The aim of this investigation was to evaluate and quantify the association of circulating GLP-1 concentration with ad libitum total calorie and macronutrient intake. METHODS: One-hundred and fifteen individuals (72 men) aged 35 ± 10 years were admitted for an inpatient study investigating the determinants of energy intake. Ad libitum food intake was assessed during 3 days using a reproducible vending machine paradigm. Fasting plasma GLP-1 concentrations were measured on the morning of the first day and on the morning of the fourth day after ad libitum feeding. RESULTS: Plasma GLP-1 concentrations increased by 14% after 3 days of ad libitum food intake. Individuals overate on average 139 ± 45% of weight-maintaining energy needs. Fasting plasma GLP-1 on day 1 was negatively associated with carbohydrate intake (r = - 0.2, p = 0.03) and with daily energy intake from low fat-high simple sugar (r = - 0.22, p = 0.016). CONCLUSION: Higher plasma GLP-1 concentrations prior to ad libitum food intake were associated with lower carbohydrate intake and lower simple sugar ingestion, indicating a possible role of the GLP-1 in the reward pathway regulating simple sugar intake. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00342732

Norepinephrine and thyroxine are predictors of fat mass gain in humans with cold-induced brown adipose tissue activation

Context: In healthy adults with detectable cold-induced brown adipose tissue activation (CIBA), the relationships between sympathetic nervous system (SNS) or thyroid activity during energy balance (EBL) with CIBA and body composition change are undetermined. Objective: To investigate the relationships between CIBA and thermoneutral catecholamines and thyroid hormones measured during EBL and to determine if CIBA, catecholamines, or thyroid hormones predict body composition changes. Design, Setting, Participants, and Interventions: Twelve healthy volunteers (seven male and five female) with positive CIBA [>2 standardized uptake value (g/mL)] had 24-hour energy expenditure (24hEE) assessed during EBL via whole-room indirect calorimetry while residing on a clinical research unit. Positron emission tomography/computed tomography scans were performed after exposure to 16 degrees C for 2 hours to quantify CIBA. Main Outcome Measures: CIBA, 24hEE during EBL, and thermoneutrality with concomitant measurement of urinary catecholamines and plasma free T3 and free T4. Body composition at baseline and 6 months by dual-energy X-ray absorptiometry. Results: Lower urinary norepinephrine and free T4 were associated with higher CIBA (r = -0.65, P = 0.03; and r = -0.75, P < 0.01, respectively), but CIBA was not associated with 24hEE at thermoneutrality (P = 0.77). Lower CIBA (beta = -3.5 kg/standardized uptake value; P < 0.01) predicted fat mass gain, whereas higher urinary norepinephrine and free T4 predicted future fat mass gain at 6 months (beta = 3.0 kg per twofold difference in norepinephrine, P = 0.03; and beta = 1.2 kg per 0.1-ng/dL difference in free T4, P = 0.03, respectively). Conclusion: Lower SNS and free thyroid measurements at baseline indicate a greater capacity for CIBA, which may be predictive against fat mass gain

Targeted deletion of Tcf7l2 in adipocytes promotes adipocyte hypertrophy and impaired glucose metabolism.

ObjectiveActivation of the Wnt-signaling pathway is known to inhibit differentiation in adipocytes. However, there is a gap in our understanding of the transcriptional network regulated by components of the Wnt-signaling pathway during adipogenesis and in adipocytes during postnatal life. The key intracellular effectors of the Wnt-signaling pathway occur through TCF transcription factors such as TCF7L2 (transcription factor-7-like 2). Several genetic variants in proximity to TCF7L2 have been linked to type 2 diabetes through genome-wide association studies in various human populations. Our work aims to functionally characterize the adipocyte specific gene program regulated by TCF7L2 and understand how this program regulates metabolism.MethodsWe generated Tcf7l2F/F mice and assessed TCF7L2 function in isolated adipocytes and adipose specific knockout mice. ChIP-sequencing and RNA-sequencing was performed on the isolated adipocytes with control and TCF7L2 knockout cells. Adipose specific TCF7L2 knockout mice were challenged with high fat diet and assessed for body weight, glucose tolerance, and lipolysis.ResultsHere we report that TCF7L2 regulates adipocyte size, endocrine function, and glucose metabolism. Tcf7l2 is highly expressed in white adipose tissue, and its expression is suppressed in genetic and diet-induced models of obesity. Genome-wide distribution of TCF7L2 binding and gene expression analysis in adipocytes suggests that TCF7L2 directly regulates genes implicated in cellular metabolism and cell cycle control. When challenged with a high-fat diet, conditional deletion of TCF7L2 in adipocytes led to impaired glucose tolerance, impaired insulin sensitivity, promoted weight gain, and increased adipose tissue mass. This was accompanied by reduced expression of triglyceride hydrolase, reduced fasting-induced free fatty acid release, and adipocyte hypertrophy in subcutaneous adipose tissue.ConclusionsTogether our studies support that TCF7L2 is a central transcriptional regulator of the adipocyte metabolic program by directly regulating the expression of genes involved in lipid and glucose metabolism

Targeted deletion of Tcf7l2 in adipocytes promotes adipocyte hypertrophy and impaired glucose metabolism

Objective: Activation of the Wnt-signaling pathway is known to inhibit differentiation in adipocytes. However, there is a gap in our understanding of the transcriptional network regulated by components of the Wnt-signaling pathway during adipogenesis and in adipocytes during postnatal life. The key intracellular effectors of the Wnt-signaling pathway occur through TCF transcription factors such as TCF7L2 (transcription factor-7-like 2). Several genetic variants in proximity to TCF7L2 have been linked to type 2 diabetes through genome-wide association studies in various human populations. Our work aims to functionally characterize the adipocyte specific gene program regulated by TCF7L2 and understand how this program regulates metabolism. Methods: We generated Tcf7l2F/F mice and assessed TCF7L2 function in isolated adipocytes and adipose specific knockout mice. ChIP-sequencing and RNA-sequencing was performed on the isolated adipocytes with control and TCF7L2 knockout cells. Adipose specific TCF7L2 knockout mice were challenged with high fat diet and assessed for body weight, glucose tolerance, and lipolysis. Results: Here we report that TCF7L2 regulates adipocyte size, endocrine function, and glucose metabolism. Tcf7l2 is highly expressed in white adipose tissue, and its expression is suppressed in genetic and diet-induced models of obesity. Genome-wide distribution of TCF7L2 binding and gene expression analysis in adipocytes suggests that TCF7L2 directly regulates genes implicated in cellular metabolism and cell cycle control. When challenged with a high-fat diet, conditional deletion of TCF7L2 in adipocytes led to impaired glucose tolerance, impaired insulin sensitivity, promoted weight gain, and increased adipose tissue mass. This was accompanied by reduced expression of triglyceride hydrolase, reduced fasting-induced free fatty acid release, and adipocyte hypertrophy in subcutaneous adipose tissue. Conclusions: Together our studies support that TCF7L2 is a central transcriptional regulator of the adipocyte metabolic program by directly regulating the expression of genes involved in lipid and glucose metabolism. Keywords: Diabetes, Adipose tissue, Obesity, Wnt signaling, Lipolysi

Behavioral and technological interventions targeting glycemic control in a racially/ethnically diverse population: a randomized controlled trial

BACKGROUND: Diabetes self-care by patients has been shown to assist in the reduction of disease severity and associated medical costs. We compared the effectiveness of two different diabetes self-care interventions on glycemic control in a racially/ethnically diverse population. We also explored whether reductions in glycated hemoglobin (HbA1c) will be more marked in minority persons. METHODS: We conducted an open-label randomized controlled trial of 376 patients with type 2 diabetes aged ≥18 years and whose last measured HbA1c was ≥7.5% (≥58 mmol/mol). Participants were randomized to: 1) a Chronic Disease Self-Management Program (CDSMP; n = 101); 2) a diabetes self-care software on a personal digital assistant (PDA; n = 81); 3) a combination of interventions (CDSMP + PDA; n = 99); or 4) usual care (control; n = 95). Enrollment occurred January 2009-June 2011 at seven regional clinics of a university-affiliated multi-specialty group practice. The primary outcome was change in HbA1c from randomization to 12 months. Data were analyzed using a multilevel statistical model. RESULTS: Average baseline HbA1c in the CDSMP, PDA, CDSMP + PDA, and control arms were 9.4%, 9.3%, 9.2%, and 9.2%, respectively. HbA1c reductions at 12 months for the groups averaged 1.1%, 0.7%, 1.1%, and 0.7%, respectively and did not differ significantly from baseline based on the model (P = .771). Besides the participants in the PDA group reporting eating more high-fat foods compared to their counterparts (P < .004), no other significant differences were observed in participants’ diabetes self-care activities. Exploratory sub-analysis did not reveal any marked reductions in HbA1c for minority persons but rather modest reductions for all racial/ethnic groups. CONCLUSIONS: Although behavioral and technological interventions can result in some modest improvements in glycemic control, these interventions did not fare significantly better than usual care in achieving glycemic control. More research is needed to understand how these interventions can be most effective in clinical practice. The reduction in HbA1c levels found in our control group that received usual care also suggests that good routine care in an integrated healthcare system can lead to better glycemic control. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01221090