Is regular exercise an effective strategy for weight loss maintenance?

Weight regain after weight loss is one of the most significant challenges to successful obesity treatment. Regular exercise has long been touted as a strategy for weight loss maintenance, but the lack of clear evidence in clinical trials has caused some to question its effectiveness. In this review, we present the arguments both questioning and in support of exercise as an obesity therapeutic. Our purpose is to bring clarity to the literature, present a unified perspective, and identify the gaps in knowledge that need to be addressed in future studies. Critical questions remain including sex differences, individual variability and compensatory behaviors in response to exercise, exercise adherence, the role of energy flux and the molecular mechanisms mediating the beneficial effects of exercise after weight loss and during weight regain. Future research should focus on these critical questions to provide a more complete understanding of the potential benefits of exercise on weight loss maintenance.

Early infant adipose deposition is positively associated with the n-6 to n-3 fatty acid ratio in human milk independent of maternal BMI.

BACKGROUND/OBJECTIVES: Excessive infant weight gain in the first 6-month of life is a powerful predictor of childhood obesity and related health risks. In mice, omega-6 fatty acids (FAs) serve as potent ligands driving adipogenesis during early development. The ratio of omega-6 relative to omega-3 (n-6/n-3) FA in human milk (HM) has increased threefold over the last 30 years, but the impact of this shift on infant adipose development remains undetermined. This study investigated how maternal obesity and maternal dietary FA (as reflected in maternal red blood cells (RBCs) composition) influenced HM n-6 and n-3 FAs, and whether the HM n-6/n-3 ratio was associated with changes in infant adipose deposition between 2 weeks and 4 months postpartum. SUBJECTS/METHODS: Forty-eight infants from normal weight (NW), overweight (OW) and obese (OB) mothers were exclusively or predominantly breastfed over the first 4 months of lactation. Mid-feed HM and maternal RBC were collected at either transitional (2 weeks) or established (4 months) lactation, along with infant body composition assessed using air-displacement plethysmography. The FA composition of HM and maternal RBC was measured quantitatively by lipid mass spectrometry. RESULTS: In transitional and established HM, docosahexaenoic acid (DHA) was lower (P=0.008; 0.005) and the arachidonic acid (AA)/DHA+eicosapentaenoic acid (EPA) ratio was higher (P=0.05; 0.02) in the OB relative to the NW group. Maternal prepregnancy body mass index (BMI) and AA/DHA+EPA ratios in transitional and established HM were moderately correlated (P=0.018; 0.001). Total infant fat mass was increased in the upper AA/DHA+EPA tertile of established HM relative to the lower tertile (P=0.019). The amount of changes in infant fat mass and percentage of body fat were predicted by AA/EPA+DHA ratios in established HM (P=0.038; 0.010). CONCLUSIONS: Perinatal infant exposures to a high AA/EPA+DHA ratio during the first 4 months of life, which is primarily reflective of maternal dietary FA, may significantly contribute to the way infants accumulate adipose.

The role for adipose tissue in weight regain after weight loss.

Weight regain after weight loss is a substantial challenge in obesity therapeutics. Dieting leads to significant adaptations in the homeostatic system that controls body weight, which promotes overeating and the relapse to obesity. In this review, we focus specifically on the adaptations in white adipose tissues that contribute to the biological drive to regain weight after weight loss. Weight loss leads to a reduction in size of adipocytes and this decline in size alters their metabolic and inflammatory characteristics in a manner that facilitates the clearance and storage of ingested energy. We present the hypothesis whereby the long-term signals reflecting stored energy and short-term signals reflecting nutrient availability are derived from the cellularity characteristics of adipose tissues. These signals are received and integrated in the hypothalamus and hindbrain and an energy gap between appetite and metabolic requirements emerges and promotes a positive energy imbalance and weight regain. In this paradigm, the cellularity and metabolic characteristics of adipose tissues after energy-restricted weight loss could explain the persistence of a biological drive to regain weight during both weight maintenance and the dynamic period of weight regain.

Adaptations of leptin, ghrelin or insulin during weight loss as predictors of weight regain: a review of current literature.

Numerous laboratory studies involving both animal and human models indicate that weight loss induces changes in leptin, ghrelin and insulin sensitivity, which work to promote weight regain. It is unclear, however, whether these biological changes serve as a biomarker for predicting weight regain in free-living humans in which biological, behavioral and environmental factors are likely at play. We identified 12 studies published between January 1995 and December 2011 that reported changes in leptin, ghrelin or insulin during intentional weight loss with a follow-up period to assess regain. Two of the nine studies examining leptin suggested that larger decreases were associated with greater regain, three studies found the opposite (smaller decreases were associated with greater regain), whereas four studies found no significant relationship; none of the studies supported the hypothesis that increases in ghrelin during weight loss were associated with regain. One study suggested that improvements in insulin resistance were associated with weight gain, but five subsequent studies reported no association. Changes in leptin, ghrelin or insulin sensitivity, taken alone, are not sufficient to predict weight regain following weight loss in free-living humans. In future studies, it is important to include a combination of physiological, behavioral and environmental variables in order to identify subgroups at greatest risk of weight regain.

Treatment related factors and inhibitor development in children with severe haemophilia A.

With the advent of modern factor replacement therapy the most important remaining obstacle to successful treatment in haemophilia A is the development of inhibitory antibodies against Facto VIII (FVIII). This retrospective case control study examined genetic variables and early treatment patterns in severe haemophilia A patients who subsequently developed clinically significant inhibitors to FVIII compared with matched controls who did not. Seventy eight inhibitor patients were identified from 13 UK centers over 25 years (1982-2007). For each case an age matched control was selected. Data on potential genetic and treatment related risk factors were collected for cases and controls. Treatment related data was collected for the first 50 exposure days (EDs) for controls or up to inhibitor development for cases. Risk factors were compared for significance by univariate and multivariate analysis. Of the genetic risk factors, major defects in the FVIII gene and non-caucasian ethnicity were each responsible for approximately 5-fold increases in inhibitor risk. When treatment related variables are considered, high intensity treatment increased inhibitor risk around 2.5 fold whether represented by the presence of peak treatment moments or by high overall treatment frequency. This finding was significant regardless of the timing of the high intensity treatment. Periods of intense treatment associated with surgery for porta-cath insertion were however not found to be associated with increased inhibitor risk. No association was shown between inhibitor development and age at first FVIII exposure, type of FVIII product, or the use of regular prophylaxis. This study confirms treatment-related factors as important risks for inhibitor development in Haemophilia A.

Ideal body weight correlates better with engraftment after PBSC autograft than actual body weight, but is under-estimated in myeloma patients possibly due to disease-related height loss.

Stem cell dose is important in determining rate of engraftment following autograft. We show closer correlation with haematopoietic reconstitution when the CD34+ cell dose is calculated using ideal (IBW) rather than actual (ABW) body weight in 218 patients receiving peripheral blood stem cell (PBSC) autograft for haematological malignancy. ABW was 21% greater than IBW thus the median CD34+ dose of 5.0 x 10(6)/kg (ABW) rose to 6.1 x 10(6)/kg when calculated by IBW. Neutrophils reached 0.5 x 10(9)/l in 11 days (range 8-21), while platelets reached 20 x 10(9)/l unsupported in 12 days (range 7-38). For both neutrophil and platelet engraftment, a greater inverse correlation was seen when IBW was used to calculate stem cell dose (r2=0.082 vs r2=0.104 for neutrophils and r2=0.085 vs r2=0.135 for platelets). Those non-myeloma patients who failed to achieve a CD34+ dose of 4 x 10(6) cells/kg by ABW but did so by IBW achieved neutrophil and platelet engraftment not significantly different from those who achieved that stem cell dose by both methods. This was not confirmed in patients treated for myeloma, possibly owing to inaccurate IBW in patients with skeletal height loss. We confirm that calculation of CD34+ cell dose by IBW safely predicts engraftment for patients with haematological malignancies other than myeloma undergoing PBSC autograft.

Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase.

Skeletal muscle GLUT-4 transcription in response to treatment with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), a known activator of AMP-activated protein kinase (AMPK), was studied in rats and mice. The increase in GLUT-4 mRNA levels in response to a single subcutaneous injection of AICAR, peaked at 13 h in white and red quadriceps muscles but not in the soleus muscle. The mRNA level of chloramphenicol acyltransferase reporter gene which is driven by 1,154 or 895 bp of the human GLUT-4 proximal promoter was increased in AICAR-treated transgenic mice, demonstrating the transcriptional upregulation of the GLUT-4 gene by AICAR. However, this induction of transcription was not apparent with 730 bp of the promoter. In addition, nuclear extracts from AICAR-treated mice bound to the consensus sequence of myocyte enhancer factor-2 (from -473 to -464) to a greater extent than from saline-injected mice. Thus AMP-activated protein kinase activation by AICAR increases GLUT-4 transcription by a mechanism that requires response elements within 895 bp of human GLUT-4 proximal promoter and that may be cooperatively mediated by myocyte enhancer factor-2.

Plasma cholesteryl ester transfer protein activity is not linked to insulin sensitivity.

Plasma cholesteryl ester transfer protein (CETP) activity has been reported to decline during a hyperinsulinemic-euglycemic clamp. It has been suggested that this suppressive effect of acute hyperinsulinemia is linked to whole body insulin sensitivity, and that the insulin resistance that accompanies obesity leads to high plasma CETP activity found in obese subjects. In the present study, we used 2 experimental approaches to examine the putative link between CETP and insulin action. First, we examined if the clamp-induced suppression of plasma CETP activity is linked to whole body insulin sensitivity. Plasma CETP activity was measured at the beginning and end of a 2-hour hyperinsulinemic-euglycemic clamp in 18 nondiabetic individuals before and after an exercise training regimen that improved insulin sensitivity without weight loss. CETP activity decreased in response to the clamp procedure in 16 of 18 subjects, and on average, by 9% (P <.001). While training decreased plasma CETP activity (10%, P <.05), the improvement in insulin sensitivity had no statistical effect on the clamp-induced suppression of plasma CETP activity (training*clamp, P =.26). Second, we examined if insulin resistance is associated with an elevation in fasting plasma CETP activity when the influence of adiposity and diabetes were negated. Plasma CETP activity was measured in 41 women (12 insulin-sensitive lean; 8 insulin-resistant lean; 10 insulin-sensitive obese; 11 insulin-resistant obese). The level of insulin sensitivity had no significant effect on fasting plasma CETP activity, but CETP levels were 25% higher in obese subjects (P <.01). Thus, neither experimental approach provided evidence that plasma CETP levels are linked to insulin and insulin sensitivity. These data suggest that the elevated CETP activity found in obese patients is less associated with hyperinsulinemia and the accompanying insulin resistance, but rather is more related to some other metabolic complication of obesity.

Muscle glucose transporter (GLUT 4) gene expression during exercise.

Among the many effects of exercise is the induction of glucose transporter (GLUT 4) expression in skeletal muscle. In this review, we examine the intracellular signals that may mediate the exercise-induced increase in GLUT4 gene transcription. This induction is likely to be dependent upon intracellular calcium concentrations and the energy charge of the muscle.

Insulin does not regulate the promoter of cholesteryl ester transfer protein (CETP) in HIRc/pCETP-CAT cells.

Cholesteryl ester transfer protein (CETP) is a plasma enzyme involved in cholesterol metabolism. As a potential target in the treatment of atherosclerosis, a number of studies have focused how this enzyme is regulated. It has been postulated that insulin may regulate CETP gene expression, and these effects may be mediated through CCAAT/enhancer binding protein alpha (C/EBPalpha). The present study examines the effects of insulin on the activity of the CETP promoter in rat fibroblasts expressing the human insulin receptor (HIRc). HIRc cells were stably transfected with a chimeric construct containing 3.2 kb of the CETP promoter attached to the bacterial chloramphenicol acyltransferase gene (pCETP-CAT) without significantly affecting the expression of the insulin receptor. CAT activity was 8-fold higher in cultured HIRc/pCETP-CAT in the presence of 100 mg/dL LDL cholesterol, than those cultured without cholesterol (p < 0.05). However, culturing these cells in the presence of 100 nM insulin did not result in any change in CAT activity when compared to control cells. In HIRc/pCETP-CAT cells transiently transfected with a construct that constitutively expressed C/EBPalpha protein, a 3-fold increase in CAT activity was observed when compared to cells transiently transfected with non-specific DNA (p < 0.05). However, no observable effect on the CETP promoter was observed in the presence of insulin. Thus, in HIRc/pCETP-CAT cells, we were unable to substantiate the hypothesis that insulin regulates CETP gene transcription. These results suggest that the effects of insulin on CETP expression regulation may be downstream of transcription.

Differential expression of cholesteryl ester transfer protein in the liver and plasma of fasted and fed transgenic mice.

Because cholesteryl ester transfer protein (CETP) is considered a potential target in the treatment of atherosclerosis, several reports have focused on the regulation of this enzyme, and there is evidence that insulin may be a regulatory factor. The present study examines the differential expression of the human CETP gene between physiologic conditions that are accompanied by low (fasted) and high (fed) insulin levels. CETP expression was examined in plasma and tissues of transgenic mice expressing the human CETP minigene after 12 hours of fasting (n = 20) or ad libitum feeding (n = 20) with normal mouse chow. Plasma cholesteryl ester transfer activity (CETA) was 20% higher in fed than in fasted mice, reflecting higher levels of CETP (P < 0.05). This observation was accompanied by higher liver mRNA in fed mice (100%, P < 0.05), as determined by ribonuclease protection assays, as well as by higher CETA (23%, P < 0.05) and CETP mass (29%, P < 0.05) in the particulate fraction of liver homogenates. These parameters of liver CETP expression correlated well with each other, as well as with plasma CETA. CETP in the liver particulate fraction was found as a doublet (approximately 70 and 65 kDa), which resolved to a single band (approximately 60 kDa) upon deglycosylation. No differences in CETP expression were observed in pooled adipose tissue samples from fed and fasted mice. Insulin and glucose were not related to any plasma or tissue parameter of CETP expression. In summary, the concerted, differential expression of CETP in the liver of fed and fasted transgenic mice appears to contribute to higher plasma CETP levels in fed mice, but the precise role of insulin and glucose in regulating CETP expression under fasted and fed conditions needs to be defined.

Effect of short-term exercise training on leptin and insulin action.

The purpose of the study was to determine the effect of short-term exercise training (7 consecutive days for 60 min/d at 75% maximal oxygen consumption [VO2 max]), which did not change body mass on fasting plasma leptin concentration and insulin action. Young, lean subjects (n = 16; age, 21.9 +/- 0.6 years; body fat, 17.5% +/- 1.5%) and older subjects with relatively more adipose tissue (n = 14; age, 58.6 +/- 1.4 years; body fat, 28.3% +/- 1.3%) were studied (mean +/- SE). Fasting plasma leptin was significantly (P < .05) related to adiposity (fat mass, r = .58; % body fat, r = .76) in this population. Body mass did not change (P < .05) in any of the groups with training (71.8 +/- 2.5 v 71.9 +/- 2.5 kg). The insulin sensitivity index (SI determined from an intravenous glucose tolerance test (IVGTT) improved significantly (P < .05) in both the young group (4.8 +/- 0.6 v6.9 +/- 0.8 x 10(-4)/ min (microU/mL) and the older group (3.2 +/- 0.6 v 5.9 +/- 1.0 x 10(-4)/min (microU/mL)). Fasting leptin did not change with training in either group (10.4 +/- 1.6 v 9.2 +/- 1.0 ng/mL). These findings suggest that exercise does not independently affect the fasting plasma leptin concentration and the improvement in insulin action with exercise is not associated with an alteration in fasting leptin in healthy sedentary lean and relatively lean subjects.

Lipoprotein subpopulation distributions in lean, obese, and type 2 diabetic women: a comparison of African and white Americans.

OBJECTIVE: Abnormal subpopulation distributions of plasma lipoproteins have been reported in white American (WA) women with obesity and type 2 diabetes that explain part of the elevated rate of cardiovascular disease in these patients. This study examined if these perturbations also occur in obese and diabetic African American (AA) women and compared the lipoprotein profiles with WA counterparts. RESEARCH METHODS AND PROCEDURES: We determined the lipoprotein subpopulation distribution in the plasma of 51 lean women (29 WA, 22 AA, body mass index [BMI] < 30), 50 obese women (27 WA, 23 AA, BMI > 30), and 43 obese women with type 2 diabetes (27 WA, 16 AA), by nuclear magnetic resonance spectroscopy. RESULTS: AA diabetic women, like WA diabetic women, had a larger average very low density lipoprotein (VLDL) size, elevated levels of small low density lipoprotein cholesterol (LDL-C), and lower levels of small high density lipoprotein cholesterol (HDL-C), when compared to lean controls (p<0.05). These differences were accompanied by higher VLDL-triglycerides (TG) and LDL-C in WA (p<0.05), but not in AA. Although the effects of obesity and diabetes on lipoprotein subpopulation were fairly similar for AA and WA, some racial differences, particularly with respect to HDL, were observed. DISCUSSION: The atherogenic perturbations in lipoprotein profiles of obese AA women, particularly those with diabetes, were relatively similar to those found in WA women and may be contributing to the increased rate of cardiovascular disease (CVD) in AA with obesity and diabetes. The parameters of subpopulation distribution may provide better markers for CVD than lipid concentrations alone, particularly in AA women. Furthermore, subtle racial differences in lipoprotein profiles suggest that race-specific criteria may be needed to screen patients for CVD.

Impact of insulin resistance on lipoprotein subpopulation distribution in lean and morbidly obese nondiabetic women.

The purpose of this study was to examine the effects of insulin resistance on the lipoprotein subpopulation distribution of very-low-density, low-density, and high-density lipoproteins (VLDL, LDL, and HDL) in lean and morbidly obese nondiabetic women. Lean women (body mass index [BMI], 20 to 27 kg/m2) stratified by BMI were divided into insulin-sensitive (SL, n = 12) and insulin-resistant (RL, n = 8) groups according to Bergman's minimal model, SI. A group of obese women (BMI, 30 to 53 kg/m2), also stratified by BMI, were divided into insulin-sensitive (SO, n = 10) and insulin-resistant (RO, n = 11) groups in a similar fashion. Resistant groups were similar to sensitive groups (SL v RL and SO vRO) in age, weight, percent body fat, and waist circumference, ie, total and regional adiposity. VLDL, LDL, and HDL subpopulation distributions were determined in fasting plasma samples by nuclear magnetic resonance (NMR) spectroscopy. The average particle sizes of all 3 classes of lipoproteins were similar for the SL and RL groups. In contrast, RO subjects had larger VLDL, smaller LDL, and smaller HDL, than SO subjects (P < .05). Lower concentrations of large LDL and large HDL were found in RO compared with SO subjects (P < .05). In obese women, but not in lean women, VLDL size was associated with plasma insulin (r = .60, P < .005), while LDL size and HDL size were negatively correlated with plasma insulin (r = -.39, P < .05 and r = -.38, P < .05) and positively correlated with SI (r = .54, P < .01 and r = .42, P < .05). These results suggest that in obese women, insulin resistance may be involved in the formation of lipoprotein subpopulation distributions that are associated with vascular disease.

Caffeine decreases malonyl-CoA in isolated perfused skeletal muscle of rats.

The regulation of acetyl-CoA carboxylase and malonyl-CoA levels in skeletal muscle may involve a calcium-dependent mechanism. To examine the effects of increased free sarcoplasmic calcium concentrations on malonyl-CoA in skeletal muscle, isolated hindlimbs of rats were perfused for 30 min with a medium containing bovine red blood cells, bovine serum albumin, 200 microU/ml insulin, and 10 mM glucose in Krebs-Henseleit buffer and caffeine at 0, 0.12, 0.5, or 3 mM. Malonyl-CoA decreased from control (no caffeine) values of 1.34 +/- 0.9 to 0.95 +/- 0.12 pmol/mg in gastrocnemius-plantaris muscles perfused with 0.12 and 0.5 mM caffeine and to 0.63 +/- 0.07 pmol/mg in the muscles perfused with 3 mM caffeine. Adenosine 3',5'-cyclic monophosphate (cAMP) increased from 0.24 +/- 0.02 to 0.32 +/- 0.04 nmol/g, and AMP decreased from 83 +/- 8 to 53 +/- 3 nmol/g in response to 3 mM caffeine. Citrate and ATP were unaffected by caffeine. A decline in malonyl-CoA with 0.12 and 0.5 mM caffeine without an increase in cAMP supports the hypothesis that a calcium-dependent mechanisms of acetyl-CoA carboxylase and malonyl-CoA regulation exists, but a cAMP-dependent mechanism may also be involved with 3 mM caffeine.

Effect of fasting and refeeding on acetyl-CoA carboxylase in rat hindlimb muscle.

Previous studies have demonstrated marked differences in liver acetyl-CoA carboxylase (ACC) activity between fasted rats and fasted rats refed with a fat-free diet. This study was designed to determine whether skeletal muscle ACC responds to dietary manipulation similarly to liver. Male Sprague-Dawley rats were fasted 48 h (F), fasted 48 h and refed fat-free diet for 48 h (R), or were fed normal rat chow ad libitum (A). Liver ACC, measured on resuspended ammonium sulfate precipitates of 48,000 g supernatants of tissue homogenates, was markedly decreased in F (77 +/- 6 nmol.g-1.min-1) and increased in R (562 +/- 37 nmol.g-1.min-1) rats compared with A rats (210 +/- 23 nmol.g-1.min-1). The citrate concentration required to cause half-maximal activation of liver ACC (K0.5) was 1.34 +/- 0.14 mM for F, 0.77 +/- 0.09 mM for R, and 0.87 +/- 0.09 mM for A. The quadriceps muscle, on the other hand, showed no difference in ACC activity or in the K0.5 for citrate activation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blots confirmed the biochemical measurements, showing marked differences in the size of the protein bands in the +260,000 mol wt range in F vs. R liver ACC preparations but not in skeletal muscle ACC preparations. We conclude that skeletal muscle ACC is controlled by different mechanisms than those observed in liver.

Role of epinephrine during insulin-induced hypoglycemia in fasted rats.

Responses to insulin-induced hypoglycemia in fasted sham-operated (SHAM), adrenodemedullated (ADM), and epinephrine-infused ADM (ADM + E) rats were studied to ascertain the specific role of epinephrine in increasing resting skeletal muscle content of adenosine 3',5'-cyclic monophosphate (cAMP) and fructose 2,6-bisphosphate (F-2,6-P2), which are involved in stimulation of muscle glycogenolysis and lactate production. Rats from each group were fasted for 24 h and then infused intravenously with insulin (30, 60, or 90 min) to produce plasma insulin values of approximately 92 microU/ml. One-half of the insulin-infused ADM rats were also infused with epinephrine (ADM + E). Muscle and blood lactate, muscle cAMP, and muscle F-2,6-P2 increased and muscle glycogen decreased in SHAM rats. Each of these changes was prevented or attenuated in ADM rats and restored in ADM + E rats. Liver cAMP, glycogen, and F-2,6-P2 responses to hypoglycemia were similar in SHAM, ADM, and ADM + E rats. Blood glucose decreased to 0.74 +/- 0.05 mM in ADM rats compared with 1.54 +/- 0.11 mM in SHAM and 1.34 +/- 0.15 mM in ADM + E rats after 90 min of insulin infusion. The increase in plasma epinephrine is therefore essential in the counterregulatory response to insulin-induced hypoglycemia in fasted rats. Resting skeletal muscle glycogenolysis and lactate production for hepatic gluconeogenic substrate appear to be important components of the counterregulatory response in fasted rats.

Correlation between fructose 2,6-bisphosphate and lactate production in skeletal muscle.

The epinephrine-induced production of lactate in nonexercising muscles may be due in part to allosteric activation of 6-phosphofructo-1-kinase by fructose 2,6-bisphosphate (F-2,6-P2). To determine if a correlation exists between F-2,6-P2 and lactate production in skeletal muscle, isolated rat hindlimbs were perfused for 30 min with a medium containing epinephrine at concentrations varying between 1.7 +/- 0.5 and 72.4 +/- 4.2 nM. In comparison to control values, hindlimbs perfused with 72.4 +/- 4.2 nM epinephrine had a two- to threefold increase in F-2,6-P2 and a fourfold increase in muscle lactate production. Hindlimb lactate production was highly correlated to gastrocnemius adenosine 3',5'-cyclic monophosphate (r = 0.80), fructose 6-phosphate (r = 0.87), and F-2,6-P2 (r = 0.81). The adenosine 3',5'-cyclic monophosphate-mediated increase in glycogenolysis with consequent increase in fructose 6-phosphate (substrate for 6-phosphofructo-1-kinase and 6-phosphofructo-2-kinase) is likely important for induction of lactate production by inactive muscle. The high correlation between muscle F-2,6-P2 and muscle lactate production at varying concentrations of epinephrine supports the hypothesis that the epinephrine-induced activation of glycolysis and lactate production in nonexercising muscle is mediated in part by increases in F-2,6-P2 levels.