Fat as an endocrine organ: How obesity causes disease

1. Fat as an endocrine organ: How obesity causes disease

2. Obesity: an excess of body fat frequently resulting in a significant impairment of health

3. Prevalence of Obesity in USA

7. Ideal body condition score

8. Ideal body condition score

11. Developed by Ellen KienzleDeveloped by Ellen Kienzle

12. Assessing obesity: Breed Diversity

14. Body fat in different breeds at a BCS of 5-6

17. Diseases associated with obesity: Dogs Arthritis Hip dysplasia Ruptured cruciate Congestive heart failure Dyspnea Dermatitis Anal Sac disease Hyperlipidemia Hypertension Hypothyroidism Diabetes mellitus Cushing�s disease Cancer

18. Diseases associated with obesity in cats Diabetes mellitus FLUTD Asthma Dyspnea Hepatic lipidosis Allergic dermatitis Deep pyoderma Constipation

20. P<0.001 is derived from wilcoxon signed rank test. Lean-fed dogs lived a median of 15% (1.8 years) longer than control dogs. Median life span (the age at which 50% of the dogs in the group were deceased) was 11.2 years in the control group vs. 13.0 years in the lean-fed group. A survival plot is simply expressed as one of two things: either cumulative survival with time (decimal or percent) or cumulative mortality with time (decimal or percent). They reflect the same thing.P<0.001 is derived from wilcoxon signed rank test. Lean-fed dogs lived a median of 15% (1.8 years) longer than control dogs. Median life span (the age at which 50% of the dogs in the group were deceased) was 11.2 years in the control group vs. 13.0 years in the lean-fed group. A survival plot is simply expressed as one of two things: either cumulative survival with time (decimal or percent) or cumulative mortality with time (decimal or percent). They reflect the same thing.

22. A variety of chronic diseases developed as dogs aged. The most common diagnosis was osteoarthritis (43 dogs; diagnosis made radiographically). A variety of chronic diseases developed as dogs aged. The most common diagnosis was osteoarthritis (43 dogs; diagnosis made radiographically).

25. How does obesity cause �disease�?

26. Metabolic Syndrome HUMANS Visceral obesity Insulin resistance Hypertension Chronic inflammation Thrombotic disorders Endothelial dysfunction Atherosclerosis Dogs and Cats Obesity Insulin resistance Chronic Inflammation And Arthritis Diabetes mellitus

27. IGF-1 = Insulin-like Growth Factor-1; IL= Interleukin ; PAI-1 = Plasminogen activator inhibitor-1; SAA = serum amyloid A; TNF-alpha = Tumor Necrosis Factor-alpha; TGF-beta = Transforming Growth Factor � beta; C3 = Complement protein 3IGF-1 = Insulin-like Growth Factor-1; IL= Interleukin ; PAI-1 = Plasminogen activator inhibitor-1; SAA = serum amyloid A; TNF-alpha = Tumor Necrosis Factor-alpha; TGF-beta = Transforming Growth Factor � beta; C3 = Complement protein 3

28. Glucose uptake and insulin action in human adipose tissue, influence of BMI, anatomical depot and body fat distribution Lean individuals had similar insulin responsiveness in omental and SC fat Adipose tissue from overweight and obese individuals is insulin resistant Insulin resistance occurs at a lower BMI than expected Obese subjects with central adiposity have insulin resistance in omental tissue, peripherally obese subjects do not. Solic M, Russell A, Hutley L, et al Int J Obes relat Metab Disord 2002 Jan:26(1):17-23

29. The players

30. Resistin is a hormone secreted from visceral adipose Resistin directly antagonizes insulin in the liver Increases glycogenolysis and insulin resistance DIABETES MELLITUS Resistin

31. Surgical removal of visceral fat reverses hepatic insulin resistance Diabetes 1999;48:94-98 Removal of visceral fat pads (VF) resulted in marked decreases in leptin (by 60%) and TNF-alpha (by 72%) Restored insulin sensitivity of the liver

32. Increased visceral AT Adiponectin deficiency Adiponectin helps insulin work in muscle and fat Impairment of glucose utilization peripherally DIABETES MELLITUS

33. Increased leptin caused by increased visceral abdominal tissue Leptin is abnormal when secreted by VAT vs SCAT Leptin resistance develops in brain HUNGER

34. Leptin and VAT vs SCAT Int J Obes Relat Metab Disord 1997; 21 (8): 708-711 Leptin highly correlated with BMI and SQ fat Leptin activity was inversely correlated with visceral fat and visceral to SQ ratio

35. Plasma leptin in obese dogsIshioka, 2002: J Vet Med Sci Dogs fed a high energy diet for 3 months showed significant increases in plasma leptin which correlated with fat mass Leptin concentrations in 59 client owned dogs correlated positively with BCS Mean plasma leptin was significantly increased (12.3 ng/ml) in dogs with BCS (5/5) compared with ideal BCS dogs (2.7 ng/ml)

36. Other players Visfatin Glucocorticoids Free fatty acids Angiotensinogen TNF-alpha Interleukin 6 Plasminogen-Activator Inhibitor 1

37. Glucocorticoids Obese patients have normal levels of glucocorticoids in serum Increased visceral adipocyte expression of 11-beta-hydroxysteroid dehydrogenase Results in increased LOCAL production of glucocorticoids in visceral fat Contributes to metabolic syndrome: insulin resistance locally (liver)

38. Free Fatty Acids Elevated in viscerally obese individuals Adipokines Facilitate hyperinsulinemia, lipotoxicity and beta cell apoptosis Insulin resistance in muscle and liver mediated by FFA metabolites such as acyl-CoA

39. TNF IL-6 Proinflammatory adipokine Stimulates leptin and IL-6 Suppresses adiponectin Stimulates lipolysis Correlated with insulin resistance Immune modulating cytokine Released from visceral adipose tissue Stimulates hepatic C reactive protein Inhibits insulin action in muscle, liver and adipocytes

40. Other players TNF-alpha PAI-1 Angiotensinogen IL-beta TGF-beta Interleukin 6

41. Interleukin 6 Inflammatory mediator Produced from adipose tissue Causes recruitment of macrophages and other inflammatory cells Key player in immune reactions

42. Angiotensinogen Secreted from visceral adipose tissue Positively correlated with body fat mass Promotes vascular inflammation in addition to its effects on body fluid Angiotensin II stimulates adipogenesis and lipogenesis ACE inhibitors block these effects Beneficial in preventing type 2 DM

43. TNF-alpha Produced by excessive fat Inflammatory mediator Causes insulin resistance Recruitment of inflammatory cells Diabetes mellitus, arthritis, hypertension ensues

44. Pink = blood; light green = cell cytosol. White blob is insulin. Black asterisk = glucosePink = blood; light green = cell cytosol. White blob is insulin. Black asterisk = glucose

45. Pink = blood; light green = cell cytosol. White blob is insulin. Black asterisk = glucosePink = blood; light green = cell cytosol. White blob is insulin. Black asterisk = glucose

46. How does obesity lead to type 2 DM? Insulin resistance Resistin Lack of adiponectin Leptin resistance Impaired insulin secretion High carbohydrate diets GLP-1 deficiency

47. Background: Feline nutrition Cats are strict carnivores Cats have tremendous ability to synthesize glucose from protein via gluconeogenesis The feline liver has normal hexokinase but no glucokinase activity Cats have limited ability to �mop up� excess glucose and store glycogen Human patients with type 2 DM show impaired hepatic glucokinase activity

48. Do high carbohydrate diets contribute to type 2 DM? Backus 2007 ACVIM 2 colonies of cats 25 females�dry diet only�(high C) 10 females, 8 males---canned food only (low C) Decreased insulin sensitivity as body fat and age increased Decreased insulin secretion AUC (0-15) in cats fed dry diets

49. Metabolic Hallmarks of Type II Diabetes Mellitus Impaired insulin secretion Acute insulin response reduced or absent Second phase of insulin secretion is delayed and exaggerated Caused by: Down regulation of glucose receptors�glucose toxicity? Glucagon-like peptide 1 deficiency?

50. Impaired insulin secretion in feline DM Rand, 1998 Diabetic cats: Show early impaired insulin secretion followed by exaggerated second phase Normal cats: Show early rise in insulin secretion

51. Abn regulation of HGP in mice with a disrupted GK allele Rossetti: Am Physiol Soc: 1997:E743-750 Comparison of GK deletion (pancreatic/hepatic) mice compared with wild type and pancreatic GK deleted mice Hyperglycemia suppressed HGP only 12% in GK deleted mice compared with 45% WT and PGK deleted mice Insulin secretion impaired in both GK deleted mice compared with WT

52. What is the role of GLUT-1 vs GLUT-4 receptors in the progression from obesity to DM? Hoenig 2006 Female cats that became obese from ad libitum feeding (dry food) Decreased expression of GLUT-4 receptors during obesity Decreased insulin sensitivity First change prior to glucose intolerance

53. Pathogenesis of type 2 DM

54. How does obesity lead to osteoarthritis? Increased inflammatory mediators TNF-alpha Angiotensinogen IL-1 beta Oxidative stress Activation of arachidonic cascade

55. Mechanisms of Disease: Obesity Adipose tissue is characterized by inflammation and progressive infiltration by macrophages as obesity develops Figure 1 (Source: Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J. Clin. Invest. 112:1785�1788 (2003).Figure 1 (Source: Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J. Clin. Invest. 112:1785�1788 (2003).

56. Oxidative Stress & Obesity Source of illustration: Furukawa, et al. The Journal of Clinical Investigation http://www.jci.org Volume 114 Number 12 December 2004 Source of illustration: Furukawa, et al. The Journal of Clinical Investigation http://www.jci.org Volume 114 Number 12 December 2004

57. Inflammatory Mediators in OA Arthritis is an inflammatory condition. Interleukin 1 beta and tumor necrosis factor alpha both trigger the release of MMPs, as does leukotriene B4. In addition, IL-1B stimulates the COX2 enzyme. The COX (cyclooxygenase) enzymes are the rate limited enzymes in eicosanoid production. During arthritis, the COX-2 enzyme is induced by IL-1 and other triggers. COX-2 results in dramatically increased production of Prostaglandin E2. PGE2 further stimulates MMP production directly and via further stimulation of TNF-a and IL-1 B. In addition, PGE2 stimulate pain receptors, contributing to the pain of arthritis. In dogs, PGE2 levels are positively correlated with degree of lameness from arthritis.Arthritis is an inflammatory condition. Interleukin 1 beta and tumor necrosis factor alpha both trigger the release of MMPs, as does leukotriene B4. In addition, IL-1B stimulates the COX2 enzyme. The COX (cyclooxygenase) enzymes are the rate limited enzymes in eicosanoid production. During arthritis, the COX-2 enzyme is induced by IL-1 and other triggers. COX-2 results in dramatically increased production of Prostaglandin E2. PGE2 further stimulates MMP production directly and via further stimulation of TNF-a and IL-1 B. In addition, PGE2 stimulate pain receptors, contributing to the pain of arthritis. In dogs, PGE2 levels are positively correlated with degree of lameness from arthritis.

59. Conclusions: Obesity is the root of many metabolic diseases! Fat cells produce hormones and inflammatory mediators which cause a variety of diseases including osteoarthritis in dogs and diabetes mellitus in cats Treatment of the underlying cause (i.e. obesity) is key to treating the clinical signs of the disease (OA, DM) itself

62. Rate of Weight Loss in Dogs

64. Feeding for Weight Loss Use computer software Or calculate starting intake, e.g. 70% x MER at ideal weight Dogs, average MER = 110 Body weight (Kg) 0.75 Cats, average MER = 55* Body weight (Kg) Estimate ideal weight based on BCS, or set target for ~15 to 20% less than current Recheck & adjust monthly Deviation from average Metabolic response to energy restriction and decreased body mass

65. Protein in Weight Management Independent of other effects, protein needs to be increased simply to meet normal requirements: Food intake usually reduced to contribute to calorie restriction = need increased nutrient/calorie ratio Reduced protein sparing CHO and fat energy sources = more protein oxidized for energy Increased protein preserves lean body mass

66. Protein in Weight Management Post prandial heat increment (kJ/7 hr) Difference in TEF was 39 � 40 Kcal/ 7 hr. (TEF prot = 62 +/- 14; CHO = 22 +/- 16; Fat 23 +/- 17). Assuming this difference twice daily equals an annual difference of 29200 Kcal/year. AT 3600 Kcal/lb, this is 8.11 lb/year. If 3500Kcal/lb, then 8.3 lb/yr.Difference in TEF was 39 � 40 Kcal/ 7 hr. (TEF prot = 62 +/- 14; CHO = 22 +/- 16; Fat 23 +/- 17). Assuming this difference twice daily equals an annual difference of 29200 Kcal/year. AT 3600 Kcal/lb, this is 8.11 lb/year. If 3500Kcal/lb, then 8.3 lb/yr.

67. Protein and Wt. Loss: ResultsLoss of Lean and Fat in Cats

68. Protein in Weight Management From Hoenig 2007 Fig. 1. Average heat production (kcal/h) in lean cats fed either high-carbohydrate/low-protein (HC, n = 5; ) or high-protein/low-carbohydrate (HP, n = 5; ) diet. The value at time 0 is the average heat production during the 2-h baseline period. The cats were fed at time 0 and monitored for an additional 22 h. From Hoenig 2007 Fig. 1. Average heat production (kcal/h) in lean cats fed either high-carbohydrate/low-protein (HC, n = 5; ) or high-protein/low-carbohydrate (HP, n = 5; ) diet. The value at time 0 is the average heat production during the 2-h baseline period. The cats were fed at time 0 and monitored for an additional 22 h.

69. Protein and Wt. Loss: ResultsLoss of Lean and Fat in Dogs

70. Recap: Key Points about Obesity Obesity is most common form of malnutrition in dogs & cats Even a moderate degree of excess weight can be detrimental to health Key nutrients helpful in obesity management include: LOW fat and energy HIGH protein HIGH or Moderate fiber Water? Pharmaceutic managment

71. MTP Inhibitors

73. MTP Inhibitor Requires monthly dosage adjustments Response variable in clinical trial 0 to 20% over 16 weeks

74. Tip #1: Use a Body Condition Score System for All Patients

75. Educate clients about obesity Use illustrated BCS Demonstrate BCS to client

77. Tips to Increase Exercise in Cats Place food bowl at opposite end of house from cat�s favorite sleep area Leash train to walk on harness Increase interactive play Interact with owner Mobile toys, laser lights �Food balls�

79. Limiting Access to Food in Multi-cat Households Feed pets separately and pick up bowls between meal times Leave low calorie food available ad lib and supplement lean cats Use limited access feeding stalls

80. Cat Creep feeder from Richard HillCat Creep feeder from Richard Hill