WHY CAN T I GET SKINNY

1. WHY CAN�T I GET SKINNY??? Tracey Green MD INNERTHIN LLC.

2. Our �LIFE� Experiences Shape Our Perception After a hug, our perception of that individual changes. If we didn�t like them before and they give a meaningful hug, our perception changes because they made us feel good. If I complement someone��.I like your shoes, what beautiful eyes you have�.they change their perception. We can also change our interpretation and perception of things that in the past have caused us stress. This is called reframing. I used to not like writing papers but now I love it. It gives me a chance to grow and express my feelings. Tell study of teachers who were told that have of their class was gifted and the other half was not. Those kids who were perceived to be smarter, did better.After a hug, our perception of that individual changes. If we didn�t like them before and they give a meaningful hug, our perception changes because they made us feel good. If I complement someone��.I like your shoes, what beautiful eyes you have�.they change their perception. We can also change our interpretation and perception of things that in the past have caused us stress. This is called reframing. I used to not like writing papers but now I love it. It gives me a chance to grow and express my feelings. Tell study of teachers who were told that have of their class was gifted and the other half was not. Those kids who were perceived to be smarter, did better.

4. TWO TYPES OF PHYSICIANS 1.Those that prescribe medicines to treat the problems 2. Those that treat the problems to not prescribe medicine

5. I think we can all agree that treating blood pressure and cholesterol saves lives.

6. Cardiovascular Mortality Risk Doubles With Each 20/10 mm Hg BP Increment* Throughout middle and old age, a person�s usual blood pressure (BP) is strongly and directly related to cardiovascular disease (CVD) mortality, with no evidence of a threshold, down to at least 115/75 mm Hg. In this meta-analysis, information was obtained regarding the usual BP and causes of death for 1 million adults without known CVD at the time of enrollment in 61 prospective, observational BP studies. The analysis involved a correction for potential regression dilution bias by relating mortality during each decade of age at death to the estimated usual BP at the start of that decade. Throughout the BP range >115/75 mm Hg to 175/105 mm Hg, usual BP was found to be more strongly related to CVD than previously estimated. At ages 40-69 years, each increase of 20 mm Hg usual systolic BP (or 10 mm Hg usual diastolic BP) was associated with more than double the rate of stroke death and double the rate of death from coronary heart disease (CHD) and other vascular causes. The age-specific associations were similar for men and women. Extrapolating from these data, a 10 mm Hg lower usual systolic BP or a 5 mm Hg lower usual diastolic BP throughout middle age would be associated with an approximate 40% lower risk of stroke death and an approximate 30% lower risk of death from CHD. References Chobanian AV et al. JAMA. 2003;289:2560-2572. Lewington S et al. Lancet. 2002;360:1903-1913. Throughout middle and old age, a person�s usual blood pressure (BP) is strongly and directly related to cardiovascular disease (CVD) mortality, with no evidence of a threshold, down to at least 115/75 mm Hg. In this meta-analysis, information was obtained regarding the usual BP and causes of death for 1 million adults without known CVD at the time of enrollment in 61 prospective, observational BP studies. The analysis involved a correction for potential regression dilution bias by relating mortality during each decade of age at death to the estimated usual BP at the start of that decade. Throughout the BP range >115/75 mm Hg to 175/105 mm Hg, usual BP was found to be more strongly related to CVD than previously estimated. At ages 40-69 years, each increase of 20 mm Hg usual systolic BP (or 10 mm Hg usual diastolic BP) was associated with more than double the rate of stroke death and double the rate of death from coronary heart disease (CHD) and other vascular causes. The age-specific associations were similar for men and women. Extrapolating from these data, a 10 mm Hg lower usual systolic BP or a 5 mm Hg lower usual diastolic BP throughout middle age would be associated with an approximate 40% lower risk of stroke death and an approximate 30% lower risk of death from CHD. References Chobanian AV et al. JAMA. 2003;289:2560-2572. Lewington S et al. Lancet. 2002;360:1903-1913.

7. Relationship Between SBP Reduction and CV Mortality is Unequivocal Relationship Between SBP Reduction and CV Mortality In this slide we see a meta-analysis of a large number of outcomes studies performed in hypertensive patients. This clearly demonstrates that reducing systolic BP decreases cardiovascular mortality and confirms that the greater the reduction in systolic BP, the greater the cardiovascular benefit. � Reference: Staessen JA, et. al. Cardiovascular Protection and Blood Pressure Reduction: a Meta-analysis. Lancet 2001;358:1305-1315. Relationship Between SBP Reduction and CV Mortality In this slide we see a meta-analysis of a large number of outcomes studies performed in hypertensive patients. This clearly demonstrates that reducing systolic BP decreases cardiovascular mortality and confirms that the greater the reduction in systolic BP, the greater the cardiovascular benefit. � Reference: Staessen JA, et. al. Cardiovascular Protection and Blood Pressure Reduction: a Meta-analysis. Lancet 2001;358:1305-1315.

8. Aggressively Lowering Your High LDLCan Reduce Your Risk Markedly(risks calculated for people 45-64 years old)

10. Obesity and Hypertension

11. Obesity and Cardiovascular Risk

12. So what do we do????? Medication vs. Lifestyle

13. BOTH

14. �Obesity treatment and behavior change are too hard. I don�t have time to do this in my clinic.�

15. �Doc, I am fat because my hormones are out of whack. I know I don�t eat too much. Can you check out what�s wrong with me and give me a pill to fix it..�

16. Be the change you wish to see in the world

17. GUIDE FOR WEIGHT LOSS

18. Obesity is a disorder of excess fat accumulation , not overeating, and not sedentary behavior. Taubes (2010)

19. The body is either in a state of FAT STORAGE OR USING FAT FOR ENERGY The Goal of weight loss is to keep the body USING FAT FOR ENERGY!!!!!!!!

20. Patterns of Body Fat Distribution Just a few words about obesity. There are basically two varieties, gynecoid or female pattern obesity in the lower body and arms and male pattern or android obesity. They have dramatically different effects on the metabolic syndrome and the predisposition to it. Just a few words about obesity. There are basically two varieties, gynecoid or female pattern obesity in the lower body and arms and male pattern or android obesity. They have dramatically different effects on the metabolic syndrome and the predisposition to it.

21. Visceral Fat Distribution And this is just a CT scan through a normal person with mostly organs and � organs with a little bit of scattered omental fat and Type 2 diabetes. You can see that their waist size might not be much different here, but in this person there�s a lot � sort of packed � the abdomen is packed with fat. And this is just a CT scan through a normal person with mostly organs and � organs with a little bit of scattered omental fat and Type 2 diabetes. You can see that their waist size might not be much different here, but in this person there�s a lot � sort of packed � the abdomen is packed with fat.

22. Apples vs Pears The reasons for differences in body fat distribution are not absolutely clear. Men are more apt to develop visceral or upper-body obesity�the classic �apple� shape�while women tend to have lower-body obesity or the �pear� shape. Thus, in the pathogenesis of visceral obesity, androgens appear to be a factor. Interestingly, women with polycystic ovarian syndrome have hyperandrogenemia and develop the characteristic visceral obesity.1 Body fat distribution also may be influenced by corticosteroids and growth hormones, which promote the uptake of fatty acids into adipose tissue located in the upper body.1 Fat storage abnormalities have been noted to occur in conjunction with visceral obesity. Fat that is concentrated in the abdomen is not held as tightly as it is in other areas of the body; consequently, abdominal adipose tissue appears to release excess fatty acids into the circulation. The resultant overload of fat that accumulates in tissues is theorized to lead to insulin resistance. Conversely, in Cushing disease or other forms of hyper-corticoidism, the level of insulin resistance exceeds the degree of obesity; however, excess adiposity, when it does occur, still gravitates to the abdomen.2 Whether one chooses to believe that insulin resistance precedes upper body fat or vice versa, the fact is that obesity plays an integral part of insulin resistance�and persons with low body fat rarely display insulin resistance.1  1. Grundy SM. Metabolic complications of obesity. Endocrine. 2000;13:155-165. 2. The University of Texas Southwestern Medical Center at Dallas Center For Human Nutrition.Metabolic  Syndrome. Available at: http://swnt240.swmed.edu/humannutrition/Features/metabolicsyndrome.htm.  Apples vs Pears The reasons for differences in body fat distribution are not absolutely clear. Men are more apt to develop visceral or upper-body obesity�the classic �apple� shape�while women tend to have lower-body obesity or the �pear� shape. Thus, in the pathogenesis of visceral obesity, androgens appear to be a factor. Interestingly, women with polycystic ovarian syndrome have hyperandrogenemia and develop the characteristic visceral obesity.1 Body fat distribution also may be influenced by corticosteroids and growth hormones, which promote the uptake of fatty acids into adipose tissue located in the upper body.1 Fat storage abnormalities have been noted to occur in conjunction with visceral obesity. Fat that is concentrated in the abdomen is not held as tightly as it is in other areas of the body; consequently, abdominal adipose tissue appears to release excess fatty acids into the circulation. The resultant overload of fat that accumulates in tissues is theorized to lead to insulin resistance. Conversely, in Cushing disease or other forms of hyper-corticoidism, the level of insulin resistance exceeds the degree of obesity; however, excess adiposity, when it does occur, still gravitates to the abdomen.2 Whether one chooses to believe that insulin resistance precedes upper body fat or vice versa, the fact is that obesity plays an integral part of insulin resistance�and persons with low body fat rarely display insulin resistance.1 1. Grundy SM. Metabolic complications of obesity. Endocrine. 2000;13:155-165. 2. The University of Texas Southwestern Medical Center at Dallas Center For Human Nutrition.Metabolic Syndrome. Available at: http://swnt240.swmed.edu/humannutrition/Features/metabolicsyndrome.htm.

23. Relationship Between Visceral Adipose Tissue and Insulin Action And this is a particularly metabolically adverse type of fat. And this just shows amount of visceral adipose tissue here. The CT scan�s showing a lot of visceral adipose. And here is a lean individual and you can see that this is glucose disposal, so worsening insulin resistance or improving glucose disposal has lower amounts of fat and there�s a fairly good correlation. And this is a particularly metabolically adverse type of fat. And this just shows amount of visceral adipose tissue here. The CT scan�s showing a lot of visceral adipose. And here is a lean individual and you can see that this is glucose disposal, so worsening insulin resistance or improving glucose disposal has lower amounts of fat and there�s a fairly good correlation.

24. WHAT DRIVES FAT STORAGE??

25. What drives fat storage ????

26. FAT STORAGE

27. Intake of carbohydratesCarbohydrates are Digested to Glucose Glucose enters cells to be converted to ATP for energy Excess glucose is converted to glycogen + fat.

28. Glucose doesn�t enter cells on its own. Glucose enters via the glucose receptor protein embedded in cell membranes. Insulin �unlocks the gate� (binds to and opens the receptor) to let glucose into the cell. The major function of insulin is to counter the concerted action of a number of hyperglycemia-generating hormones and to maintain low blood glucose levels. Because there are numerous hyperglycemic hormones, untreated disorders associated with insulin generally lead to severe hyperglycemia and shortened life span. In addition to its role in regulating glucose metabolism, insulin stimulates lipogenesis, diminishes lipolysis, and increases amino acid transport into cells. Insulin also modulates transcription, altering the cell content of numerous mRNAs. It stimulates growth, DNA synthesis, and cell replication, effects that it holds in common with the insulin-like growth factors (IGFs) and relaxin. Insulin is synthesized as a preprohormone in the �-cells of the islets of Langerhans. Its signal peptide is removed in the cisternae of the endoplasmic reticulum and it is packaged into secretory vesicles in the Golgi, folded to its native structure, and locked in this conformation by the formation of 2 disulfide bonds. Specific protease activity cleaves the center third of the molecule, which dissociates as C peptide, leaving the amino terminal B peptide disulfide bonded to the carboxy terminal A peptide. Insulin secretion from �-cells is principally regulated by plasma glucose levels. Increased uptake of glucose by pancreatic �-cells leads to a concomitant increase in metabolism. The increase in metabolism leads to an elevation in the ATP/ADP ratio. This in turn leads to the inhibition of an ATP-sensitive potassium channel� (KATP channel). The net result is a depolarization of the cell leading to Ca2+ influx and insulin secretion. The KATP channel is a complex of 8 polypeptides comprising four copies of the protein encoded by the ABCC8 (ATP-binding cassette, sub-family C, member 8) gene and four copies of the protein encoded by the KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11) gene. The ABCC8 encoded protein is also known as the sulfonylurea receptor (SUR). The KCNJ11 encoded protein forms the core of the KATP channel and is called Kir6.2. As might be expected, the role of KATP channels in insulin secretion presents a viable therapeutic target for treating hyperglycemia due to insulin insufficiency as is typical in type 2 diabetes. The major function of insulin is to counter the concerted action of a number of hyperglycemia-generating hormones and to maintain low blood glucose levels. Because there are numerous hyperglycemic hormones, untreated disorders associated with insulin generally lead to severe hyperglycemia and shortened life span. In addition to its role in regulating glucose metabolism, insulin stimulates lipogenesis, diminishes lipolysis, and increases amino acid transport into cells. Insulin also modulates transcription, altering the cell content of numerous mRNAs. It stimulates growth, DNA synthesis, and cell replication, effects that it holds in common with the insulin-like growth factors (IGFs) and relaxin. Insulin is synthesized as a preprohormone in the �-cells of the islets of Langerhans. Its signal peptide is removed in the cisternae of the endoplasmic reticulum and it is packaged into secretory vesicles in the Golgi, folded to its native structure, and locked in this conformation by the formation of 2 disulfide bonds. Specific protease activity cleaves the center third of the molecule, which dissociates as C peptide, leaving the amino terminal B peptide disulfide bonded to the carboxy terminal A peptide. Insulin secretion from �-cells is principally regulated by plasma glucose levels. Increased uptake of glucose by pancreatic �-cells leads to a concomitant increase in metabolism. The increase in metabolism leads to an elevation in the ATP/ADP ratio. This in turn leads to the inhibition of an ATP-sensitive potassium channel� (KATP channel). The net result is a depolarization of the cell leading to Ca2+ influx and insulin secretion. The KATP channel is a complex of 8 polypeptides comprising four copies of the protein encoded by the ABCC8 (ATP-binding cassette, sub-family C, member 8) gene and four copies of the protein encoded by the KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11) gene. The ABCC8 encoded protein is also known as the sulfonylurea receptor (SUR). The KCNJ11 encoded protein forms the core of the KATP channel and is called Kir6.2. As might be expected, the role of KATP channels in insulin secretion presents a viable therapeutic target for treating hyperglycemia due to insulin insufficiency as is typical in type 2 diabetes.

29. INSULIN unlocks the cell surface receptor (GLUT 4) to let glucose enter. Insulin, secreted by the �-cells of the pancreas, is directly infused via the portal vein to the liver, where it exerts profound metabolic effects. These effects are the response of the activation of the insulin receptor which belongs to the class of cell surface receptors that exhibit intrinsic tyrosine kinase activity (see Signal Transduction). The insulin receptor is a heterotetramer of 2 extracellular a-subunits disulfide bonded to 2 transmembrane �-subunits. With respect to hepatic glucose homeostasis, the effects of insulin receptor activation are specific phosphorylation events that lead to an increase in the storage of glucose with a concomitant decrease in hepatic glucose release to the circulation as diagrammed below (only those responses at the level of glycogen synthase and glycogen phosphorylase are represented). Insulin, secreted by the �-cells of the pancreas, is directly infused via the portal vein to the liver, where it exerts profound metabolic effects. These effects are the response of the activation of the insulin receptor which belongs to the class of cell surface receptors that exhibit intrinsic tyrosine kinase activity (see Signal Transduction). The insulin receptor is a heterotetramer of 2 extracellular a-subunits disulfide bonded to 2 transmembrane �-subunits. With respect to hepatic glucose homeostasis, the effects of insulin receptor activation are specific phosphorylation events that lead to an increase in the storage of glucose with a concomitant decrease in hepatic glucose release to the circulation as diagrammed below (only those responses at the level of glycogen synthase and glycogen phosphorylase are represented).

30. Effects of insulin on GLUT4 in the muscle and fat Stimulation of uptake, utilization and storage of glucose. The major transporter for uptake of glucose is GLUT4. GLUT4 is translocated to the plasma membrane through the action of insulin. Insulin stimulates the fusion of GLUT4 vesicles with the plasma membrane. When blood levels of insulin decrease, the GLUT4 transporters are recycled back into the cytoplasm. Glucose is liberated from dietary carbohydrate such as starch or sucrose by hydrolysis within the small intestine, and is then absorbed into the blood. Elevated concentrations of glucose in blood stimulate release of insulin, and insulin acts on cells throughout the body to stimulate uptake, utilization and storage of glucose. The effects of insulin on glucose metabolism vary depending on the target tissue. Two important effects are: Insulin facilitates entry of glucose into muscle, adipose and several other tissues. The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters. In many tissues - muscle being a prime example - the major transporter used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin. In the absence of insulin, GLUT4 glucose transporters are present in cytoplasmic vesicles, where they useless for transporting glucose. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficienty take up glucose. When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm. The animation to the right depicts how insulin signalling leads to translocation of glucose transporters from the cytoplasm into the plasma membrane, allowing glucose (small blue balls) to enter the cell. Click on the "Add Glucose" button to start it. It should be noted here that there are some tissues that do not require insulin for efficient uptake of glucose: important examples are brain and the liver. This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent. Glucose is liberated from dietary carbohydrate such as starch or sucrose by hydrolysis within the small intestine, and is then absorbed into the blood. Elevated concentrations of glucose in blood stimulate release of insulin, and insulin acts on cells throughout the body to stimulate uptake, utilization and storage of glucose. The effects of insulin on glucose metabolism vary depending on the target tissue. Two important effects are: Insulin facilitates entry of glucose into muscle, adipose and several other tissues. The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters. In many tissues - muscle being a prime example - the major transporter used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin. In the absence of insulin, GLUT4 glucose transporters are present in cytoplasmic vesicles, where they useless for transporting glucose. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficienty take up glucose. When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm. The animation to the right depicts how insulin signalling leads to translocation of glucose transporters from the cytoplasm into the plasma membrane, allowing glucose (small blue balls) to enter the cell. Click on the "Add Glucose" button to start it. It should be noted here that there are some tissues that do not require insulin for efficient uptake of glucose: important examples are brain and the liver. This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent.

33. FAT STORAGE Storage start with acetyl-COA formation Reaction is irreversible once initiated Regulation of acetyl-COA FORMATION INSULIN

38. FAT BREAKDOWN (Lipolysis) Fat is primarily composed of Triacylglycerols (TAG) �triglycerides in adipose tissue Constitutes 84% of stored energy In adipose tissue TAGs must be hydrolyzed to fatty acids plus glycerol to be used for energy Hormone- sensitive-lipase is the enzyme that initiates the breakdown of TAG INSULIN BLOCKS HORMONE- SENSITIVE- LIPASE Insulin blocks the breakdown of fat

40. Insulin is the primary regulator of fat storage and breakdown. When insulin levels are elevated-either chronically or after a meal-we accumulate fat in the fat tissue. When insulin levels fall , we can release fat from our fat tissue and use it for fuel.

41. Increase glucose in diet��? More insulin ? Fat storage activated? Fat breakdown inhibited

44. What is the best way to lower insulin levels!!!!!!!!!!!!!!!!!! CARBOHYDRATE RESTRICTIOIN

45. By stimulating insulin secretion, carbohydrates make us fat and ultimately cause obesity. The fewer carbs we consume, the leaner we will be. Taubes (GOOD CALORIES BAD CALORIES)

47. Not all carbs created equal Pure glucose(simple sugars) has the greatest insulin response Amount of carbohydrates matters Starch + protein, fat, fiber ? less insulin response and slowed absorption of glucose (glycemic index)

48.   Simple Sugar (SS]+ or - Soluble Dietary Fiber (SDF)

52. A DIET OF CARBOHYDRATE RESTRICTION HAS MANY BENEFITS. Less fat storage less LDL cholesterol 4. HDL increases Improved glycemic control Decreases fatty liver stores 7. Reverses Metabolic Syndrome!!

58. GOUT

60. Low-carb Diet Fallout �should anything unfortunate happen to you--"even moles in [your] front lawn," as the New York physician Blake Donaldson, an early proponent of carbohydrate-restricted diets, noted in his 1961 memoirs--everyone will blame it on your diet. This past winter, I was anxious (as I will be next winter) that I would slip on an icy sidewalk, as Dr. Robert Atkins did, and crack my head open, thus prompting some chortling among critics and book reviewers that my fall was actually the result of a fat-induced coronary. � -Gary Taubes in Prevention magazine

70. Ketogenesis Acetyl-CoA derived from fatty acid oxidation enters the Citrate Cycle only if carbohydrate metabolism is properly balanced. When fatty acid oxidation produces more acetyl-CoA than can be combined with OAA to form citrate, then the "extra" acetyl-CoA is converted to acetoacetyl-CoA and ketone bodies, including acetone. Ketogenesis (synthesis of ketone bodies) takes place primarily in the liver.