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Paul S MacLean

Publications and source records attributed to Paul S MacLean.

12 recordsLinked to original sources
PubMed2025

A consensus guide to preclinical indirect calorimetry experiments.

Understanding the complex factors influencing mammalian metabolism and body weight homeostasis is a long-standing challenge requiring knowledge of energy intake, absorption and expenditure. Using measurements of respiratory gas exchange, indirect calorimetry can provide non-invasive estimates of whole-body energy expenditure. However, inconsistent measurement units and flawed data normalization methods have slowed progress in this field. This guide aims to establish consensus standards to unify indirect calorimetry experiments and their analysis for more consistent, meaningful and reproducible results. By establishing community-driven standards, we hope to facilitate data comparison across research datasets. This advance will allow the creation of an in-depth, machine-readable data repository built on shared standards. This overdue initiative stands to markedly improve the accuracy and depth of efforts to interrogate mammalian metabolism. Data sharing according to established best practices will also accelerate the translation of basic findings into clinical applications for metabolic diseases afflicting global populations.

Calorimetry, Indirect↗
PubMed2006

Trafficking of dietary fat in obesity-prone and obesity-resistant rats.

The trafficking of dietary fat was assessed in obesity-prone (OP) and obesity-resistant (OR) male and female rats. Test meals containing [1-(14)C]palmitate were delivered through gastric feeding tubes while rats consumed a high-carbohydrate diet (HCD) or after 5 days of a high-fat diet (HFD). Over the subsequent 24 h, the appearance of (14)C was followed in the GI tract, skeletal muscles (SM), liver, adipose tissues (AT), and expired CO(2). There was no difference in the production of (14)CO(2) between OP and OR rats consuming a HCD. However, after 5 days on HFD, OR rats produced significantly more (14)CO(2) after the test meal than OP rats (P < 0.001 females, P = 0.03 males). The differential oxidation of dietary fat between OP and OR rats on HFD was not due to differences in absorption but rather was associated with preferential disposition of tracer to AT in OP rats. Measurements of lipoprotein lipase in part explained increased tracer uptake by AT in OP rats but were not consistent with increased SM tracer uptake in OR rats. Surprisingly, female rats oxidized more tracer than male rats irrespective of phenotype or diet. These results are consistent with the notion that differences in the partitioning of dietary fat between storage in AT and oxidation in SM and liver that develop shortly after the introduction of a HFD may in part underlie the differential tendency for OR and OP rats to gain weight on this diet.

Adipose Tissue↗
PubMed2006

knocking down liver ccaat/enhancer-binding protein alpha by adenovirus-transduced silent interfering ribonucleic acid improves hepatic gluconeogenesis and lipid homeostasis in db/db mice.

CCAAT/enhancer-binding protein-alpha (C/EBPalpha) is a member of the basic leucine zipper transcription factor family and regulates expression of several enzymes in the liver that control glucose and lipid metabolism. Using adenovirus-transduced silent interfering (si)RNA against C/EBPalpha, endogenous liver C/EBPalpha protein was knocked down by 70-80% in 8-wk-old wild-type (WT) and db/db mice. In WT mice, fasting blood glucose concentrations were reduced approximately 24% without changes in plasma free fatty acid and triglycerides, when compared with LacZ adenovirus-treated control mice. Ad-C/EBPalpha siRNA treatment nearly normalized fasting glucose and significantly reduced plasma insulin and free fatty acid content, even though there was no elevation of C/EBPalpha protein in the livers of db/db mice. In parallel with the changes in glucose levels, hepatic glucose production was significantly reduced in C/EBPalpha siRNA-treated WT and db/db mice. mRNA levels of phyosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and liver glycogen synthase were decreased in the C/EBPalpha siRNA-treated WT and db/db mice. Interestingly, the magnitude of reduction in these enzymes was more profound in db/db mice. C/EBPalpha siRNA also decreased mRNA levels of proliferator activator protein-gamma coactivator-1alpha in both the WT and db/db mice but reduced cAMP response element-binding protein only in WT and did not alter hepatic nuclear factor-4alpha and CBP/p300 expression. Expression of genes involved in lipogenesis, such as fatty acid synthase, acetyl-CoA carboxylase, and sterol regulatory element-binding protein-1c was robustly suppressed in the C/EBPalpha siRNA-treated db/db mice. Taken together, these results indicate that C/EBPalpha plays an important role in maintaining glucose and lipid homeostasis in the liver.

Adenoviridae↗
PubMed2006

Peripheral metabolic responses to prolonged weight reduction that promote rapid, efficient regain in obesity-prone rats.

Weight regain after weight loss is the most significant impediment to long-term weight reduction. We have developed a rodent paradigm that models the process of regain after weight loss, and we have employed both prospective and cross-sectional analyses to characterize the compensatory adaptations to weight reduction that may contribute to the propensity to regain lost weight. Obese rats were fed an energy-restricted (50-60% kcal) low-fat diet that reduced body weight by 14%. This reduced weight was maintained for up to 16 wk with limited provisions of the low-fat diet. Intake restriction was then removed, and the rats were followed for 56 days as they relapsed to the obese state. Prolonged weight reduction was accompanied by 1) a persistent energy gap resulting from an increased drive to eat and a reduced expenditure of energy, 2) a higher caloric efficiency of regain that may be linked with suppressed lipid utilization early in the relapse process, 3) preferential lipid accumulation in adipose tissue accompanied by adipocyte hyperplasia, and 4) humoral adiposity signals that underestimate the level of peripheral adiposity and likely influence the neural pathways controlling energy balance. Taken together, long-term weight reduction in this rodent paradigm is accompanied by a number of interrelated compensatory adjustments in the periphery that work together to promote rapid and efficient weight regain. These metabolic adjustments to weight reduction are discussed in the context of a homeostatic feedback system that controls body weight.

Adipose Tissue↗
PubMed2005

Suppression of hepatic cholesteryl ester transfer protein expression in obese humans with the development of type 2 diabetes mellitus.

Cholesteryl ester transfer protein (CETP) is a plasma enzyme that can modulate the profile of lipoproteins and is thus considered: 1) a mediator of vascular disease; and 2) a therapeutic target for vascular disease. In the present study, we pursued a better understanding of the effect of type 2 diabetes on the expression of CETP in obese patients. Obesity was accompanied by a 20% elevation in plasma CETP that was eliminated with the development of diabetes. These differences were observed for both men and women and were due to variations in the amount of CETP protein in the plasma. The mRNA and protein of both the full-length (CETPFL) and alternatively spliced (CETPDelta9) forms of CETP were lower in the liver, but not in either sc or omental adipose tissue depots, of diabetic obese subjects. Sterol response element binding proteins 1 and 2 were also lower in liver homogenates, suggesting that these transcription factors may mediate the effects of type 2 diabetes on hepatic CETP expression. Thus, the suppressive effects of type 2 diabetes in obese subjects are observed in both men and women and may be due, at least in part, to a suppression of hepatic CETP expression.

Adult↗
PubMed2004

Enhanced metabolic efficiency contributes to weight regain after weight loss in obesity-prone rats.

Metabolic adjustments occur with weight loss that may contribute to a high rate of weight regain. We have previously observed in obesity-prone, obese rats that weight reduction is accompanied by a suppression in resting metabolic rate beyond what would be predicted for the change in metabolic mass. In the present study, we examine if this adjustment in metabolic efficiency is affected by the length of time in weight maintenance and if it contributes to the propensity to regain after weight loss. Twenty-four-hour, nonresting, and resting energy expenditure (REE) were obtained by indirect calorimetry and normalized to metabolic mass estimated by dual-energy X-ray absorptiometry. A 10% loss in body weight in weight-reduced rats was accompanied by a 15% suppression in adjusted REE. This enhancement in metabolic efficiency was not altered with either 8 or 16 wk of weight maintenance, but it did resolve when the forced control of intake was removed and the weight was regained. The rate of weight regain increased with the time in weight maintenance and was exceptionally high early during the relapse period. During this high rate of weight gain, the suppression in REE persists while consumption increases to a level that is higher than when they were obese. In summary, an enhanced metabolic efficiency and an elevated appetite both contribute (60% and 40%, respectively) to a large potential energy imbalance that, when the forcible control of energy intake is relieved, becomes actualized and results in an exceptionally high rate of weight regain.

Animals↗
PubMed2004

Metabolic adjustments with the development, treatment, and recurrence of obesity in obesity-prone rats.

Obesity is reaching epidemic proportions and predisposes afflicted individuals to several comorbidities. For these individuals, losing weight has proven to be an easier feat than maintaining a reduced weight. In obesity-prone rats, we examined if there is a metabolic propensity to regain weight after a period of significant weight loss. Twenty-four-hour energy expenditure (EE), sleeping metabolic rate (SMR), and nonprotein respiratory quotient (NPRQ) were obtained by indirect calorimetry with urinary nitrogen analysis and normalized to fat mass (FM) and fat-free mass (FFM) acquired by dual-energy X-ray absorptiometry. Obesity-prone rats were examined after free access to a high-fat diet for 16 wk to establish the obese state. They were again examined after 2 wk of calorie restriction, which reduced body weight (14%) and FM (32%). Rats were again examined after a further 8 wk of intake-regulated weight maintenance or ad libitum feeding that led to weight regain. Metabolic data were compared with preobese and age-matched controls. Weight loss suppressed EE and SMR beyond what was expected for the change in metabolic mass. This elevated metabolic efficiency persisted throughout weight maintenance but resolved after 8 wk of regain. Adjusted NPRQ values were elevated in weight-maintained and weight-regaining rats, suggesting a preference for carbohydrate utilization. These data support the concept that weight reduction in obesity is accompanied by metabolic adjustments beyond the drive to consume calories that predispose to weight regain, and some aspects of this adjustment persist with prolonged weight maintenance and during weight regain.

Absorptiometry, Photon↗
PubMed2003

Cholesteryl ester transfer protein expression prevents diet-induced atherosclerotic lesions in male db/db mice.

OBJECTIVE: Accompanying more atherogenic lipoprotein profiles and an increased incidence of atherosclerosis, plasma cholesteryl ester transfer protein (CETP) is depressed in diabetic obese patients compared with nondiabetic obese counterparts. The depressed levels of CETP in the plasma of diabetic obese individuals may contribute to the development of an atherogenic lipoprotein profile and atherogenesis. We have examined the effect of CETP expression on vascular health in the db/db model of diabetic obesity. METHODS AND RESULTS: Transgenic mice expressing the human CETP minigene were crossed with db/db strain, and 3 groups of offspring (CETP, db, and db/CETP) were placed on an atherogenic diet for 16 weeks. The proximal aorta was then excised and examined for the presence of atherosclerotic plaques. In db mice, 9 of 11 had intimal lesions with a mean area of 26 098+/-7486 microm2. No lesions greater than 1000 microm2 were observed in db/CETP or CETP mice. CETP-expressing mice had lower circulating cholesterol concentrations than db mice. Fractionating plasma lipids by FPLC indicated that the difference in total cholesterol was primarily attributable to differences in VLDL and LDL. CONCLUSIONS: The expression of human CETP in db/db mice prevented the formation of diet-induced lesions, suggesting an antiatherogenic effect of CETP in the context of diabetic obesity.

Animals↗
PubMed2003

Skeletal muscle sterol regulatory element binding protein-1c decreases with food deprivation and increases with feeding in rats.

Sterol regulatory element binding protein-1c (SREBP-1c) is a transcription factor that responds to nutritional status and regulates metabolic gene expression in liver and adipose tissue. Although SREBP-1c RNA is expressed in skeletal muscle, little is known about its regulation in this tissue. To determine whether SREBP-1c is regulated by nutritional status in muscle, rats were food deprived for 48 h and then given access to a semipurified high cornstarch diet for 0, 6, 12 or 24 h. At each time point, blood was drawn for measurement of glucose and insulin concentrations, and the soleus, gastrocnemius and the white portion of the quadriceps muscle were removed for measurement of SREBP-1c RNA and protein. SREBP-1c RNA was increased (P < 0.05) by 6 h of refeeding and peaked at 12 h (fivefold in soleus and gastrocnemius, fourfold in white vastus) in all muscles studied. SREBP-1a RNA was not altered by refeeding. In accordance with the RNA data, the 125-kDa SREBP-1 protein increased with refeeding. To determine whether food deprivation decreased SREBP-1c RNA, rats were fed a high cornstarch diet during their normal diurnal cycle. Food was withdrawn at the beginning of the light cycle and muscles collected at 0, 6, 12 and 24 h after food was removed. SREBP-1c RNA decreased at all time points and was approximately 60% lower in the soleus and gastrocnemius and approximately 75% lower in the white quadriceps after 24 h. Additional refeeding experiments were conducted using a high fat diet in place of a high cornstarch diet. This diet diminished the increase in SREBP-1c RNA at all time points and in all muscles. This effect could not be explained by plasma glucose or insulin concentration. In conclusion, SREBP-1c RNA and SREBP-1 protein levels respond to nutritional status in skeletal muscle.

Animal Feed↗
PubMed2002

Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta.

Ablation of peroxisome proliferator activated receptor (PPAR) alpha, a lipid-activated transcription factor that regulates expression of beta-oxidative genes, results in profound metabolic abnormalities in liver and heart. In the present study we used PPAR alpha knockout (KO) mice to determine whether this transcription factor is essential for regulating fuel metabolism in skeletal muscle. When animals were challenged with exhaustive exercise or starvation, KO mice exhibited lower serum levels of glucose, lactate, and ketones and higher nonesterified fatty acids than wild type (WT) littermates. During exercise, KO mice exhausted earlier than WT and exhibited greater rates of glycogen depletion in liver but not skeletal muscle. Fatty acid oxidative capacity was similar between muscles of WT and KO when animals were fed and only 28% lower in KO muscles when animals were starved. Exercise-induced regulation and starvation-induced regulation of pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, two classical and robustly responsive PPAR alpha target genes, were similar between WT and KO in skeletal muscle but markedly different between genotypes in heart. Real time quantitative PCR analyses showed that unlike in liver and heart, in mouse skeletal muscle PPAR delta is severalfold more abundant than either PPAR alpha or PPAR gamma. In both human and rodent myocytes, the highly selective PPAR delta agonist GW742 increased fatty acid oxidation about 2-fold and induced expression of several lipid regulatory genes, including pyruvate-dehydrogenase kinase 4 and uncoupling protein 3, responses that were similar to those elicited by the PPAR alpha agonist GW647. These results show redundancy in the functions of PPARs alpha and delta as transcriptional regulators of fatty acid homeostasis and suggest that in skeletal muscle high levels of the delta-subtype can compensate for deficiency of PPAR alpha.

Animals↗
PubMed2002

Exercise-induced transcription of the muscle glucose transporter (GLUT 4) gene.

We studied the effects of exercise on GLUT4 gene transcription in several lines of transgenic mice expressing the chloramphenicol acyltransferase (CAT) reporter gene, driven by various lengths of the human GLUT4 promoter (2400, 1600, 895, and 730 bp). In all transgenic lines examined, endogenous GLUT4 mRNA increased in response to exercise (19-90%, P < 0.05). Exercise increased CAT mRNA (51-83%, P < 0.05) in mice when the transgene was driven by at least 895 bp of the promoter but showed no effect in mice in which the transgene was driven by only 730 bp. These results suggest that the exercise-induced increase in the transcriptional activity of the human GLUT4 gene is mediated, at least in part, by element(s) within -895 bp of the promoter. These observations reveal a striking similarity to the time course and regional promoter requirements of AMPK-induced GLUT4 gene expression, providing further evidence that AMPK may be mediating the effects of exercise on GLUT4 expression.

Animals↗