Progress 10/01/04 to 09/30/09
Outputs
OUTPUTS: Experiments were performed and analyzed, and results were incorporated into teaching. Experiments tested the relationships between the synthesis of lipids and the replication of new cells in adipose tissue in vivo, which may explain links between obesity, insulin resistance and diabetes, with implications for diet, genetic risk and therapeutic strategies. More specifically, experiments investigated the relationship between production of new fat cells in adipose tissue, adipose tissue lipid turnover (lipolysis and lipogenesis), and tissue insulin resistance, using new non-radioactive techniques. New dietary and pharmacologic strategies for improving metabolic status, including risk of cardiovascular disease, type 2 diabetes mellitus (T2DM) and cancer were also tested, developed and taught. These dietary strategies were tested through experiments in animals and are built around intermittent caloric restriction, or alternate day fasting. PARTICIPANTS: Nothing significant to report during this reporting period. TARGET AUDIENCES: Nothing significant to report during this reporting period. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
Changes in knowledge resulted from experiments performed. We have shown striking effects of modified alternate day fasting regimens in rodents - including reduced global cell proliferation (reducing the risk for cancer of several tissues), increased fat cell number and reduced fat cell size (associated with reduced T2DM risk) and improvements in other metabolic risk factors - and tested the degree of alternate day caloric restriction required to achieve the effects. This dietary regimen may prove useful for prevention of certain chronic diseases. More specifically,we demonstrated for the first time that the in vivo benefits in mice of classic, daily caloric restriction (including biomarkers of risk for cancer, diabetes and heart disease) can be reproduced by a) true alternate day fasting, comprising a day with no food intake alternating with a day of ad-libitum intake and b) modified alternate-day fasting, comprising a day of 15-50% of usual calorie intake alternating with a day of ad-libitum intake. The latter regimen results in no weight loss or change in body fat mass, which demonstrated for the first time that the benefits of caloric restriction regimens can be dissociated from body composition changes (i.e. can be signaled without loss of weight or fat). Knowledge about the response to dietary fat, overfeeding, exercise and other physiologic interventions was generated. Short term high-fat (HF) diet in rats or mice induced insulin resistance, based on the deuterated glucose disposal test that was developed in our laboratory. Insulin secretory response was impaired and pancreatic islet cellproliferation was also not increased in HF-fed rodents, in contrast to genetic models of insulin resistance (ob/ob mice, ZDF rats), which demonstrated markedly increased proliferation rates of pancreatic beta cells. Accordingly, HF diet impairs pancreatic beta-cell adaptation to insulin resistance. Long-term HF diet induced obesity and insulin resistance in mice. Adipogenesis correlated with the onset of insulin resistance in response to diet but not with the amelioration of insulin resistance during insulin sensitizing therapy with a PPAR-gamma agonist (glitazone). Access to running wheels resulted in a transient increase in mitochondrial biogenesis in normal rats, with female rats running longer distances and showing greater increases in new mitochondrial production than males. . Effects of different caloric restriction (CR) regimens on adipose lipid and global cell dynamics were also studied. Alternate-day fasting (ADF) increased adipose lipolysis by 50-100% and fat cell size was reduced, without reduction in serum leptin concentrations, but with reduced growth factor levels in blood. These results show that diet, exercise and drugs influence adipose dynamics and physiologic outcome measures in unpredictable ways. Direct measurements of the effects of these processes is therefore necessary, and our laboratory has developed the methods required to make these in vivo measurements.
Publications
- 12. Varady K, Roohk DJ, McEvoy-Hein BK, Gaylinn BD, Thorner MO, Hellerstein MK. Modified alternate-day fasting regimens reduce cell proliferation rates to a similar extent as daily calorie restriction in mice. FASEB J 22:2090-6, 2008. PMID: 18184721
- 9 Varady, K. and Hellerstein, M.K. 2008. Do calorie restriction or alternate-day fasting regimens modulate adipose tissue physiology in a way that reduces chronic disease risk Nutr. Rev. 66:333-342. PMID: 18522622
- 10. Pouteau, E., Turner, S., Aprikian, O., Hellerstein, M., Moser, M., Darimont, C., Fay, L.B. and Mace, K. 2008. Time course and dynamics of adipose tissue development in obese and lean Zucker rat pups. Int. J. Obes. (Lond.) 32:648-657. PMID: 18087263
- 13.Beysen C, Murphy EJ, Nagaraja H, Decaris M, Riiff T, Fong A, Hellerstein MK, Boyle PJ.J. A pilot study of the effects of pioglitazone and rosiglitazone on de novo lipogenesis in type 2 diabetes. Lipid Res. 2008 Dec;49(12):2657-63. PMID: 18641372
- 14.Varady KA, Roohk DJ, Bruss M, Hellerstein MK. Alternate-day fasting reduces global cell proliferation rates independently of dietary fat content in mice. Nutrition 2009 Apr;25(4):486-91.PMID: 19084375
- 15. Varady K, Allister CA; Roohk DJ; Hellerstein, MK. Improvements in body fat distribution and circulating adiponectin by alternate-day fasting versus calorie restriction. .J Nutr Biochem. 2009 PMID: 19195863
- 16. Stanhope K, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, Hatcher B, Cox CL, McGahan J, Seibert A, Krauss RM, Chiu S, Schaefer EJ, Ai M, Otokozawa S, Nakajima K, Nakano K, Beysen C, Hellerstein MK, Berglund L, Havel P. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 2009 May;119(5):1322-34. doi: 10.1172/JCI37385. Epub 2009 Apr 20.PMID: 19381015
- 17. Varady KA, Hudak CS, Hellerstein MK. Modified alternate-day fasting and cardioprotection: relation to adipose tissue dynamics and dietary fat intake.Metabolism. 2009 Jun;58(6):803-11.PMID: 19375762
- 18.Jaworski K, Ahmadian M, Duncan RE, Sarkadi-Nagy E, Varady KA, Hellerstein MK, Lee HY, Samuel VT, Shulman GI, Kim KH, de Val S, Kang C, Sul HS. AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency. Nat Med. 2009 Feb;15(2):159-68.PMID: 19136964
- 19.Ahmadian M, Duncan RE, Varady KA, Frasson D, Hellerstein MK, Birkenfeld AL, Samuel VT, Shulman GI, Wang Y, Kang C, Sul HS. Adipose overexpression of desnutrin promotes fatty acid use and attenuates diet-induced obesity. Diabetes. 2009 Apr;58(4):855-66. PMID: 19136649
- 20. Ahmadian M, Duncan RE, Varady KA, Frasson D, Hellerstein MK, Birkenfeld AL, Samuel VT, Shulman GI, Wang Y, Kang C, Sul HS. Adipose overexpression of desnutrin promotes fatty acid use and attenuates diet-induced obesity. Diabetes. 2009 Apr;58(4):855-66. doi: 10.2337/db08-1644. PMID: 19136649
- 21.Varady KA, Hudak CS, Hellerstein MK. Modified alternate-day fasting and cardioprotection: relation to adipose tissue dynamics and dietary fat intake. Metabolism. 2009 Jun;58(6):803-11. PMID: 19375762
- 4. Beysen, C., Murphy, E.J., McLaughlin, T., Riiff, T., Lamendola, C., Turner, H.C., Awada, M., Turner, S.M., Reaven, G. and Hellerstein, M.K. 2007. Whole-body glycolysis measured by the deuterated-glucose disposal test correlates highly with insulin resistance in vivo. Diabetes Care 30:1143-1149.
- 1. Vedala, A., Wang, W., Neese, R.A., Christiansen, M.P. and Hellerstein, M.K. 2006. Secretory pathway contributions to VLDL-triglycerides from plasma NEFA, diet, and de novo lipogenesis in humans. J. Lipid Res. 47:2562-2574.
- 2. Parks, E.J. and Hellerstein, M.K. 2006. Review series: patient-oriented research. Recent advances in liver triacylglycerol and fatty acid metabolism using stable isotope labeling techniques. J. Lipid Res. 47:1651-1660.
- 3. Turner, S.M., Roy, S., Sul, H.S., Neese, R.A., Murphy, E.J., Samandi, W., Roohk, D.J. and Hellerstein, M.K. 2007. Dissociation between adipose tissue fluxes and lipogenic gene expression in ob/ob mice. Am. J. Physiol. Endocrinol. Metab. 292:E1101- E1109.
- 5. Varady, K., Roohk, D., Loe, Y., McEvoy-Hein, B. and Hellerstein, M. 2007. Effects of modified alternate-day fasting regimens on adipocyte size, triglyceride metabolism and plasma adiponectin levels in mice. J. Lipid Res. 48:2212-2219.
- 6. Varady, K.A., Roohk, D.J. and Hellerstein, M.K. 2007. Dose effects of modified alternate-day fasting regimens on in vivo cell proliferation and plasma insulin-like growth factor-1 in mice. J. Appl. Physiol. 103:547-551.
- 7. Hellerstein, M.K. and Parks, E.J. 2007. Obesity. In: Gardner, D.G., Ed. Basic and Clinical Endocrinology. Stamford, CT: Appleton and Lange.
- 8. Varady, K.A. and Hellerstein, M.K. 2007. Alternate-day fasting and chronic disease prevention: a review of human and animal trials. Am. J. Clin. Nutr. 86:7-13.
- 11. Minehira, K., Young, S.G., Villanueva, C.J., Yetukuri, L., Oresic, M., Hellerstein, M.K., Farese, R.V. Jr., Horton, J.D., Preitner, F., Thorens, B. and Tappy, L. 2008. Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice. J. Lipid Res. 49:2038-2044.
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Progress 01/01/08 to 12/31/08
Outputs
OUTPUTS: High fat (HF) diet feeding was performed in mice and compared to chow diet, with administration of heavy water to measure the dynamics of several adipose tissue components concurrently. Increased body weight, adipose fat accumulation and triglyceride (TG) synthesis were observed. Increased adipocyte proliferation was documented, but adipocyte size nevertheless increased, which is widely agreed to be undesirable in terms of metabolic risk for disease. Thus, the increase in adipocyte proliferation was not enough to keep adipocytes small. The addition of the PPAR-gamma agonist, Rosiglitazone, which increases adipocyte proliferation in cell culture models, did not reduce fat cell size or increase adipocyte proliferation when added to HF feeding. Improved insulin sensitivity was observed within 4 days, however; thus, the improved insulin sensitivity in these models was not due to adipogenesis. Caloric restriction (CR) and alternate-day fasting (ADF) regimens were also studied in mice. A unique combination of increased lipolysis and increased lipogenesis (catabolic and anabolic pathways) was apparent in adipose tissue TG dynamics. Whole-body indirect calorimetry and food intake measurements revealed striking cyclicity on both CR and ADF diets, with intake of the entire day's food within 4-6 hours each day, resulting in an initial massive DNL (respiratory quotients [RQ] >> 1.10) followed by 16-18 hours of fat oxidation (RQ =0.7). Total fat oxidation was more than 5-fold increased on CR and ADF regimens and adipose tissue DNL was also >5-fold increased. These results are consistent with a "feast-fast" character of both CR and ADF diets. Thus, CR is a form of intermittent fasting (IF). The metabolic signals mediating CR benefits may relate to the entry of reducing units into the respiratory chain as fatty acids, not carbohydrates. The effects of single-gene manipulations in adipose tissue were also studied. Knock-out of the gene diacylglycerol-acyl transferase-1 (DGAT-1) resulted in protection against HF-induced obesity, but synthesis of adipose tissue TG was not prevented. Indeed, fractional synthesis of adipose TG was increased, not decreased, and DNL was increased above normal. Compensatory increase in flux through the enzyme DGAT-2 may account for the increase in DNL. These results suggest stimulation of flux through the DGAT2 pathway, including DNL, to compensate for DGAT1 knockout. Moreover, DGAT1 is not an absolute requirement for adipose TG synthesis. Finally, overexpression in adipose tissue of the adipose triacylglycerol lipase (termed desnutrin) resulted in higher lipolysis. Moreover, a unique pattern was observed: DNL contribution to TG was greater than total TG-glycerol turnover, the only explanation for which is TG-DG cycling (DNL-derived FAs entering without replacement of the glycerol moiety of TG). These findings are consistent with the model of hormone-sensitive lipase (DAG-lipase) being the rate-controlling step, with TG lipase providing the substrate (DAG). PARTICIPANTS: Individuals: M. Hellerstein MD PhD-PI, Cynthia Loe- Graduate student, Matt Bruss- Graduate student TARGET AUDIENCES: Nothing significant to report during this reporting period. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
The findings described above have led to a number of outcomes/impacts in the form of changes in knowledge. The role of overfeeding and lipogenesis, and the possible role of signals derived from prolonged fatty acid oxidation in the benefits of CR and ADF diets, is now a viable hypothesis that can be tested. The model that DAG-lipase (hormone-sensitive lipase) is rate-limiting in complete TAG lipolysis in adipose tissue, even though TAG-lipase is the initial step in the pathway, has been supported. The adaptive capacity of DGAT-2 to increase in flux catalyzed when DGAT-1 is absent has also been demonstrated. The inadequate adipocyte proliferative capacity of mammals such as rodents, in the face of adipose tissue hypertrophy and TAG accumulation, was directly demonstrated and the inability of PPAR-gamma agonists to stimulate adipogenesis in vivo, contrary to this effect in cell culture models, is an important result for clinical diabetes treatment.
Publications
- Varady, K. and Hellerstein, M.K. 2008. Do calorie restriction or alternate-day fasting regimens modulate adipose tissue physiology in a way that reduces chronic disease risk Nutr. Rev. 66:333-342. PMID: 18522622
- Pouteau, E., Turner, S., Aprikian, O., Hellerstein, M., Moser, M., Darimont, C., Fay, L.B. and Mace, K. 2008. Time course and dynamics of adipose tissue development in obese and lean Zucker rat pups. Int. J. Obes. (Lond.) 32:648-657. PMID: 18087263
- Minehira, K., Young, S.G., Villanueva, C.J., Yetukuri, L., Oresic, M., Hellerstein, M.K., Farese, R.V. Jr., Horton, J.D., Preitner, F., Thorens, B. and Tappy, L. 2008. Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice. J. Lipid Res. 49:2038-2044.
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Progress 01/01/07 to 12/31/07
Outputs
OUTPUTS: We have developed new dietary and pharmacologic strategies for improving metabolic status, including risk of cardiovascular disease, type 2 diabetes mellitus (T2DM) and cancer. These strategies are currently being tested in humans as well as in animal models. The dietary approach is built around intermittent caloric restriction, or alternate day fasting. We have shown striking effects of modified alternate day fasting regimens in rodents - including reduced global cell proliferation (reducing the risk for cancer of several tissues), increased fat cell number and reduced fat cell size (associated with reduced T2DM risk) and improvements in other metabolic risk factors - and tested the degree of alternate day caloric restriction required to achieve the effects. Based on the findings in rodents, we are now testing regimens consisting of a) 75% reduction in calorie intake every other day, alternating with ad-libitum intake; b) 50% reduction every other day, alternating with
ad-libitum intake; c) 30% reduction in calorie intake every day. The effects on adipose tissue dynamics, cell proliferation and insulin sensitivity are being determined after 3 months on the intervention in these people. This dietary regimen may prove useful for prevention of certain chronic diseases. In addition, human studies of agonists for peroxisome proliferator activated receptors (PPARs) are in the planning stage, including PPAR-alpha, mixed PPAR (alpha/gamma), and PPAR-delta agonists, for effects on adipose tissue dynamics, insulin resistance, blood lipids, total body water, inflammation, reverse cholesterol transport, and pancreatic beta-cell function.
PARTICIPANTS: UC Berkeley graduate students DJ Roohk, Cynthia Loe, and Matt Bruss and post-doctoral fellows Krista Varady and Carine Beysen participated on the project. Collaborators: Scott Turner PhD, E Murphy MD, PhD, E Pouteau PhD, Lisa Hudgins MD. Organizations: University of California at San Francisco; Rockefeller University; KineMed, Inc.; Nestle, Inc.
TARGET AUDIENCES: Target audiences are scientists, health-care personnel, public health personnel and the lay public, for knowledge generated.
PROJECT MODIFICATIONS: No major modifications. The emphasis has shifted somewhat to diet (caloric restriction and alternate-day feeding) and away from pharmacology (PPAR agonists), because of our recent remarkable findings with dietary strategies. We continue to study pharmacologic agents, however, and are using the same research tools as previously.
Impacts
A major outcome of our studies this past year was to advance knowledge about the beneficial consequences of modified intermittent caloric restriction regimens. We demonstrated for the first time that the in vivo benefits in mice of classic, daily caloric restriction (including biomarkers of risk for cancer, diabetes and heart disease) can be reproduced by a) true alternate day fasting, comprising a day with no food intake alternating with a day of ad-libitum intake and b) modified alternate-day fasting, comprising a day of 15-50% of usual calorie intake alternating with a day of ad-libitum intake. The latter regimen results in no weight loss or change in body fat mass, which demonstrated for the first time that the benefits of caloric restriction regimens can be dissociated from body composition changes (i.e. can be signaled without loss of weight or fat). Moreover, the modified alternate-day fasting regimens rapidly exerted beneficial effects on fat cell number and
size (increased number and reduced size within a few weeks). These discoveries open the possibility that the long-recognized benefits of classic, daily caloric restriction in animal models can finally be tested in humans with some hope of practical success, since modified alternate-day calorie restriction is likely to be much better tolerated on a long-term basis than daily semi-starvation (and does not appear to require weight loss, which has historically been difficult for people to maintain). Moreover, the biomarker tests that we have developed and used in animal models can be translated directly into humans, to assess interventions rapidly and sensitively.
Publications
- Turner, S.M., Roy, S., Sul, H.S., Neese, R.A., Murphy, E.J., Samandi, W., Roohk, D.J. and Hellerstein, M.K. 2007. Dissociation between adipose tissue fluxes and lipogenic gene expression in ob/ob mice. Am. J. Physiol. Endocrinol. Metab. 292:E1101- E1109.
- Hellerstein, M.K. and Parks, E.J. 2007. Obesity. In: Gardner, D.G., Ed. Basic and Clinical Endocrinology. Stamford, CT: Appleton and Lange.
- Varady, K.A. and Hellerstein, M.K. 2007. Alternate-day fasting and chronic disease prevention: a review of human and animal trials. Am. J. Clin. Nutr. 86:7-13.
- Beysen, C., Murphy, E.J., McLaughlin, T., Riiff, T., Lamendola, C., Turner, H.C., Awada, M., Turner, S.M., Reaven, G. and Hellerstein, M.K. 2007. Whole-body glycolysis measured by the deuterated-glucose disposal test correlates highly with insulin resistance in vivo. Diabetes Care 30:1143-1149.
- Varady, K., Roohk, D., Loe, Y., McEvoy-Hein, B. and Hellerstein, M. 2007. Effects of modified alternate-day fasting regimens on adipocyte size, triglyceride metabolism and plasma adiponectin levels in mice. J. Lipid Res. 48:2212-2219.
- Varady, K.A., Roohk, D.J. and Hellerstein, M.K. 2007. Dose effects of modified alternate-day fasting regimens on in vivo cell proliferation and plasma insulin-like growth factor-1 in mice. J. Appl. Physiol. 103:547-551.
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Progress 01/01/06 to 12/31/06
Outputs
We have measured the effects of dietary alterations, exercise and insulin sensitizing agents on dynamics of adipose tissue and other metabolic processes in vivo (including mitochondrial biogenesis, global cell proliferation and tissue insulin sensitivity). These measurements were enabled by the development over the past few years in my laboratory of stable isotope-mass spectrometric methods for measuring the flow of molecules through critical pathways in vivo in living organisms, including humans. Short-term high-fat (HF) diet in rats or mice induced insulin resistance, based on the deuterated glucose disposal test. Insulin secretory response was impaired and pancreatic islet cell proliferation was also not increased in HF-fed rodents, in contrast to genetic models of insulin resistance (ob/ob mice, ZDF rats), which demonstrated markedly increased proliferation rates of pancreatic beta cells. Accordingly, HF diet impairs pancreatic beta-cell adaptation to insulin
resistance. Long-term HF diet induced obesity and insulin resistance in mice. Adipogenesis correlated with the onset of insulin resistance in response to diet but not with the amelioration of insulin resistance during insulin-sensitizing therapy with a PPAR-gamma agonist (glitazone). Access to running wheels resulted in a transient increase in mitochondrial biogenesis in normal rats, with female rats running longer distances and showing greater increases in new mitochondrial production than males. Obese, pre-diabetic ZDF rats also ran voluntarily when exposed to running wheels and increased mitochondrial biogenesis, but treatment with a PPAR-gamma agonist (glitazone) reduced running and mitochondrial biogenesis in these animals. PPAR-gamma agonists may therefore reduce the motivation to run and reduce aerobic fitness, even as they improve insulin sensitivity. Effects of different caloric restriction (CR) regimens on adipose lipid and global cell dynamics were also studied.
Alternate-day fasting (ADF) reproduced the benefits from CR on cell proliferation (mammary, prostate, skin, T-cell proliferation were all reduced). ADF required 50-100% reduction of calorie intake on the fast day to achieve these effects. Adipose lipolysis was increased by ADF 50-100% and fat cell size was reduced, without reduction in serum leptin concentrations, but with reduced growth factor levels in blood. These results show that diet, exercise and drugs influence adipose dynamics and physiologic outcome measures in unpredictable ways. Direct measurements of the effects of these interventions on relevant metabolic processes in vivo are therefore necessary.
Impacts
Obesity and related disorders, such as insulin resistance and diabetes mellitus, are enormous and growing public health problems. The techniques and results from this project provide direct information about the underlying biology and metabolism in fat tissue in obesity in living organisms, including man. Relationships between the synthesis of lipids and other functionally important processes (such as the replication of new cells in adipose tissue, the release of circulating factors by adipose tissue, and the proliferation of mitochondria in other tissues) in vivo may explain links between obesity, insulin resistance and diabetes, with implications for diet, genetic risk and therapeutic strategies. Diet, exercise and drugs were all shown to alter the dynamics of adipose tissue components and related functional processes, but in unpredictable ways. The effects of HF diets on pancreatic beta cell proliferation, for example, or the effect of voluntary running on
mitochondrial biogenesis in obese prediabetic animals, were not obvious in advance. It is therefore necessary to measure the effects of these interventions directly, which we have been able to achieve by use of new techniques that were developed in my laboratory.
Publications
- Vedala, A., Wang, W., Neese, R.A., Christiansen, M.P. and Hellerstein, M.K. 2006. Secretory pathway contributions to VLDL-triglycerides from plasma NEFA, diet, and de novo lipogenesis in humans. J. Lipid Res. 47:2562-2574.
- Parks, E.J. and Hellerstein, M.K. 2006. Review series: patient-oriented research. Recent advances in liver triacylglycerol and fatty acid metabolism using stable isotope labeling techniques. J. Lipid Res. 47:1651-1660.
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Progress 01/01/05 to 12/31/05
Outputs
We have measured the effects of diet and insulin-sensitizing agents (PPAR-gamma agonist ligands termed glitazones) on adipose tissue turnover of cells and lipids. These measurements were made by use of the heavy water (2H2O) labeling method that we developed recently for measuring de novo lipogenesis, triglyceride synthesis and DNA replication in living organisms, including humans. Leptin administered by mini-osmotic pump to genetically obese, leptin-deficient (ob/ob) mice reduced the markedly elevated rates of adipogenesis, de novo lipogenesis, and triglyceride synthesis present in untreated mice to near-normal values, whereas caloric restriction (pair-feeding) did not alter adipose kinetics. Reduced or normal expression of lipogenic genes (by quantitative PCR of their mRNAs) in adipose tissue in these ob/ob mice did not correlate with the elevated fluxes actually present in the tissue. These studies demonstrate that this genetically obese mouse model is
characterized by markedly elevated fluxes through lipogenic and adipogenic pathways which are driven primarily by leptin deficiency, not hyperphagia, and that mRNA levels may be misleading with regard to fluxes present in vivo. Studies in rats revealed that high-fat diet leads to weight gain and increased synthesis of adipose tissue triglycerides in several adipose depots. No increase in cell proliferation was observed in the mature adipocyte fraction in response to treatment with glitazones, however, indicating that glitazones do not stimulate clonal expansion of pre-adipocytes in vivo in this model. The relation between insulin sensitivity and adipose tissue dynamics was studied by use of the 2H -glucose disposal test (2H-GDT). Glitazone treatment of ob/ob mice, Zucker fatty rats or high-fat-fed rats increased insulin sensitivity by this assay. The improvement in insulin sensitivity induced by glitazones was independent of new proliferation of mature adipocytes in high-fat fed rats.
Glitazones, like high-carbohydrate diets, increased glyceroneogenesis in rat adipose tissue, representing a mechanism for inhibiting fatty acid release from adipopose tissue into the bloodstream. These results show that the relation between adipogenesis, lipid kinetics and insulin sensitivity is complex and that PPAR-gamma agonists may act by mechanisms other than increasing adipogenesis. Human studies using the same techniques (heavy water labeling for adipose tissue dynamics and 2H-GDT for insulin sensitivity) are in progress.
Impacts
Obesity and related disorders, such as insulin resistance and diabetes mellitus, are enormous and growing public health problems. The techniques and results from this project provide direct information about the underlying biology and metabolism in fat tissue in obesity, in living organisms, including man. Relationships between the synthesis of lipids and the replication of new cells in adipose tissue in vivo may explain links between obesity, insulin resistance and diabetes, with implications for diet, genetic risk and therapeutic strategies.
Publications
- No publications reported this period
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Progress 10/01/04 to 12/31/04
Outputs
No progress to report for this period.
Impacts
No impact statement.
Publications
- No publications reported this period
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