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Adipose Tissue and Age

Adipose Tissue and Age . M.J. Hosseinzadeh (MD, PhD) School of Public Health and Institute of Public Health Research Tehran University of Medical Sciences. Fat mass and tissue distribution change dramatically throughout life. Anatomical distribution of adipose tissue.

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Adipose Tissue and Age

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  1. Adipose Tissue and Age M.J. Hosseinzadeh (MD, PhD) School of Public Health and Institute of Public Health Research Tehran University of Medical Sciences

  2. Fat mass and tissue distribution change dramatically throughout life.

  3. Anatomical distribution of adipose tissue • Subcutaneous adipose tissue : • - abdominal • - femoral • Intraabdominal adipose tissue : • - visceral (mesenteric and omental) • retroperitoneal (perirenal and • perigonadic) • Other depots : • - intra and intermuscular • - perivascular • - epicardiac Different physiological and pathogenic roles of the fat depots

  4. Middle or early old age (40–70 years) • Peak of fat mass • Advanced old age (> 70 years) • a substantial decline, with fat tissue dysfunction and redistribution to • muscle, bone marrow, liver and other tissues

  5. Cartwright et al. 2007

  6. Association of Age-related Fat Infiltration • In bone • reduced mineral density • In muscle • Development of insulin resistance • Glucose intolerance • Decreased functional capacity

  7. In old age, there is less fat where it should be and more fat where it should not be, with potential clinical consequences.

  8. the observed decrease in total body fat with old age does not coincide with a decline in percent body fat, which may remain constant or increase

  9. Increasing age: • Loss of retro-orbital and peripheral subcutaneous fat • Loss of fat from retro-orbital depots causes a sunken appearance to the eyes • Preserve of visceral fat

  10. Triceps skinfold thickness decreases after middle age particularly after age 75 • Loss of subcutaneous fat predisposes to development of • pressure sore • thermal instability • cosmetic changes

  11. high ratio of central to peripheral fat is associated with insulin resistance and increased risk of atherosclerosis and diabetes, even in lean subjects

  12. Depot-specific changes in fat tissue function with aging may contribute to development of age-related metabolic disorders

  13. Loss of fat tissue can also result in glucose intolerance potentially contributing to the paradoxical development of type II diabetes in very old, lean patients.

  14. Adipose tissue plays a central role in maintaining whole body lipid and glucose homeostasis

  15. Fat Cell Functions Insulin Sensitivity Thermogenesis Hormone Secretion

  16. Hypoplasia/ Hypotrophy: Lipodystrophy Diabetes Fat Cell Mass Dyslipidaemia Eufunction Longevity Fertility Dysfunction: Adiposopathy Glucose/Energy Homeostasis Intact Immune System Cardioprotection Diabetes Dyslipidaemia Hypertonus Hyperplasia/ Hypertrophy: Obesity Cardiovascular Morbidity Cancer

  17. White adipocytes • store excess lipid • protect other tissues from toxic accumulation of lipids • Secretion of hormones affecting whole body insulin sensitivity.

  18. Most cell dynamic research on aging has been focused on effects of aging on adipocyte replication. • Less is known about effects of aging on the capacity of cells to acquire specialized function through differentiation

  19. Adipocytes convert circulating cytotoxic free fatty acids into less damaging neutral triglycerides, thereby protecting other tissues from their lipotoxicity

  20. Age-dependent lipotoxicity is related to a decrease in adipose tissue capacity to store free fatty acids

  21. Because fat cell responsiveness to lipolytic agents decreases with increasing age declining body weight, fat mass, percent body fat, and fat cell size may be principally related to reduced capacity for lipid accumulation.

  22. Fat cell size and number are related to • insulin sensitivity • glucose and fatty acid uptake • cytokine release • Any changes in function and cellular composition of fat tissue might lead to changes in metabolic state and subsequent clinical complications

  23. The age-related decline in fat depot size is a result of decreased adipocyte size and not a decrease in cell number • New cells appear to be formed throughout the lifespan and fat cell number remains constant or increases in old age

  24. Preadipocytes are a substantial component of fat tissue, accounting for 15 to 50% of all cells

  25. Adipose tissue development : beyond adipocyte differentiation Mature adipocytes Preadipocytes Endothelial cells Mature adipocytes ADIPOCYTE HYPERTROPHY & HYPERPLASIA ANGIOGENESIS INFLAMMATION Macrophages Preadipocytes

  26. Preadipocytes cultured from old animals demonstrate a decrease in • lipid accumulation • lipogenic enzyme activities • changes in differentiation-dependent gene expression

  27. The same age-related changes are evident in colonies derived from single cells after several weeks ex vivo

  28. These findings support the hypothesis that inherent properties of preadipocytes contribute to changes in growth and function of adipose tissue with age.

  29. With aging a decrease in preadipocyte removal through differentiation into fat cells would be predicted to cause an increase in preadipocyte number.

  30. Preadipocyte capacity for lipid accumulation declines with age Differentiating preadipocytes isolated from young (3 month old), middle-aged (17 months), and old (24 months) Fischer 344 rat epididymal depots

  31. Adipose tissue growth results from two processes: • Hyperplasia • the increase in number of adipocytes that develop from precursor cells • Hypertrophy • the growth of individual fat cells due to incorporation of triglycerides

  32. White adipose tissue

  33. Adipogenesis is closely correlated with obesity and several obesity-related diseases, including • type 2 diabetes mellitus • cardiovascular disease • Hypertension • Hypercholesterolemia • Asthma • certain forms of cancer

  34. Adipogenesis is the process by which fibroblastic preadipocyte precursors are converted into fat laden adipocytes. • This process is regulated by external signals impacting on the preadipocytes as well as by an intricate network of signals and transcriptional regulators in the cells.

  35. Preadipocyte differentiation is initiated or promoted by exposure of the preadipocytes to: • Nutrients • Hormonal effectors • insulin • glucocorticoids • IGF-1 • Paracrine and autocrine effectors • free fatty acids • cyclic AMP

  36. Adipogenesis

  37. Adipogenesis is under the control of two transcription factors: • CCAAT/enhancer binding protein α (C/EBPα) • peroxisome proliferator-activated receptor γ (PPARγ)

  38. SREBP1c / ADD1 RXRa PPARb PPARg C/EBP b/d C/EBPa Wnt signaling GATA 2 & 3 Transcriptional control of adipocyte differentiation proliferation differentiation fat cell-specific gene expression J. Lipid Res., 2002, 43, 835-860

  39. Currently PPARγ is universally accepted as the master regulator that is necessary and sufficient to induce adipogenesis as no known factor can induce adipogenesis without PPARγ.

  40. Researchers at the University of Central Florida have now discovered that monocyte chemotactic protein-1 (MCP-1)-induced protein (MCPIP), can trigger adipogenesis without involvement of PPARγ. • Younce et al. JBC Papers in Press. Published on August 7, 2009

  41. MCP-1 was found to be produced, and MCPIP to be induced, before induction of PPARγ or other transcription factors in fibroblasts undergoing differentiation into adipocytes

  42. C/EBPα and PPARγ are involved in transcriptionally transactivating adipose-specific genes, including • adipocyte-specific fatty acid binding protein (aP2 or fatty acid binding protein 4) • Adiponectin • fatty acid synthase • Leptin • glucose-specific transporter 4 (GLUT4) resulting in acquisition and maintenance of the fat cell phenotype

  43. C/EBP regulates expression of key genes necessary for maintaining the fat cell phenotype • Thus C/EBP is a "bottleneck" in the chain of events beginning with activation of preadipocyte differentiation and ending with the appearance and maintenance of functional fat cells.

  44. Molecular mechanisms of age-related decreases in adipogenesis Exp Gerontol. Author manuscript; available in PMC 2008 June 1 Published in final edited form as: Exp Gerontol. 2007 June; 42(6): 463–471.

  45. Expression of C/EBPα, C/EBPδ, and PPARγ is substantially lower in differentiating preadipocytes isolated from old than from young rats

  46. Overexpression of C/EBPα in preadipocytes from old rats restores capacity to accumulate lipid and acquire the fat cell phenotype, implying that there are changes with aging in mechanisms controlling differentiation upstream of these adipogenic transcription factors.

  47. Therefore, an important change in the differentiation process with aging is the inability to maintain adequate levels of these key adipogenic regulators

  48. changes in expression of the adipogenic regulators C/EBPα, C/EBPβ -LIP, and C/EBPδ contribute to blunted differentiation with aging.

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