Chapter 2. The Physiology of Fat

Transcription

1 Chapter 2 The Physiology of Fat Obesity, generalized and localized collections of adiposity, has become endemic in the United States. It is estimated that 25-40% of US adult females and 20-25% of adult US males are obese. Over the past two decades, the incidence of obesity has doubled. Acquired and congenital focal lipodystrophies are much more common than obesity. Liposuction is the most commonly performed cosmetic surgical procedure in the United States, with somewhere between 500,000 and 750,000 procedures being performed annually by physicians of various stripes. Liposuction is also the most common surgical procedure that leads to death and morbidity. Would it not be nice to have a non-surgical procedure that could address this endemic of focal lipodystrophy? It is this intersection of prevalence and need that will propel LipoLite to become the most important clinical procedure that we have offered the cosmetic surgical consumer since the popularization of botox. It is important to understand how the LipoLite procedure manages to safely and effectively shrink focal lipodystrophies. In order to understand how LipoLite works, it is critical that we understand the mobilization of fat in the body. Fat Storage Adipose tissue, or fat, is a form of connective tissue composed of cells (adipocytes) that are separated by a matrix of collagenous and elastic fibers. One of the important physiologic roles of adipose tissue, is the storage of fuel for the body in the form of triglyerides, or fat. Body fat accumulates by filling existing adipocytes with increasing concentrations of triglycerides, causing an increase in size (hypertrophy) of each adipoctye. This adipocyte hypertrophy eventually results in convex distension of the over lying skin and the classic aesthetically displeasing focal lipodystrophies, the saddle bags, the love handles, the double chin, the spare tire, etc. If adipocyte hypertrophy becomes too pronounced, then new adipoctyes will form, a process called hyperplasia. Normally, fat stores increase from birth to maturity by a combination of hypertrophy and hyperplasia. Obese adults will commonly have billion adipocytes, compared with billion for nonobese adults. Once a fat cell is created, it may hypertrophy or shrink, but is permanent 5

2 and does not disappear. Through LipoLite we hope to shrink, through the activation of Lipolysis, the size of adipocytes in areas of focal excess fat. By contrast, Liposuction actually removes adipoctyes, a process called Lipochalasis. The principle storage or warehouse for fat is inside the adipocyte, or fat cell. Inside the adipocyte, fat is in the form of triglycerides. Trigylcerides (TG) are comprised of 3 Free Fatty Acid (FFA) molecules held to a backbone molecule of glycerol (glycerol is an ester alcohol) Most of our bodies fat is stored at TG s inside adipocytes. These adipocytes can reside in subcutaneous locations throughout the body or, in fat storage depots inside the bodies cavities, such as the omentum. Adipocytes can also reside as droplets within actual skeletal muscle cells, where they are called intramuscular triglycerides, as well as some TG s travel freely in the blood. During exercise, TG in fat cells, muscle cells and in blood can be broken down, through an important mobilization process called Lipolysis and used as fuel for oxidative phosphorylation by the exercising muscle cells. Typically 50,000 to 60,000 kcals of fat are stored throughout the body in adipocytes (most of these extracorporeal, subcutaneous adipocytes) and only kcals are stored in muscle or travel free in blood. Female and Male Fat Storage On average, women have a higher percentage of body fat than men. As the bearers and nutritional supply of newborns, this higher percentage body fat in women, was likely a teleological survival benefit. A healthy range percent body fat for a women is 20-25%, whereas for a male it is 10-15%. Obesity generally begins when men reach a percent body fat over 20% and women over 30%. Liposuction is performed on focal lipodystrophies. Focal lipodystrophies, or regional collections of fat, generally differ between male and females. Males tend to store their fat in the abdominal-truncal region, including love handles, in a pattern called android, or apple-shaped body phenotype. The android body type is associated with a higher risk for cardiovascular disease. Men also store their focal adipocytes in their breasts, gynecomastia, submentums (double chins) and in their lower lids. Women have a gynoid, or pear shaped body phenotype. In the pear shape, the focal, subcutaneous lipodystrophic adipocyte storage is on the hips, lower abdomen and thighs. LipoLite, similar to Liposuction surgery, attacks the subcutaneous adipocytes in these android and gynoid focal lipodystrophies. Metabolism and Mobilization of Fat Mobilization of fat refers to the process of releasing fat from storage sites in the body, whereas, metabolism of fat includes not only the release, but the complete biological consumption and breakdown of fat through oxidation of fat into basic energy substrates that can be utilized by the bodies cells as fuel or energy. In the LipoLite procedure, we 6

3 are most interested in the mobilization of the triglycerides out of the adipocytes, effecting an aesthetically pleasing contour change. The breakdown of triglycerides into FFA s and glyercol is a process called Lipolysis. LipoLite, if it is to be successful MUST stimulate Lipolysis, or the mobilization of TG s out of adipocytes to effect an aesthetically pleasing figure, shape and form. There are two main enzymes that regulate Lipolysis and the mobilization of FFA s: 1. Hormone sensitive Lipase (HSL) 2. Lipoprotein Lipase (LPL) Hormone Sensitive Lipase HSL is located inside the adipocyte and one of its strongest stimuli is hormone epinephrine. Epinephrine, which is released by the sympathetic nervous system (and is also in some mesotherapy cocktails), during exercise or stress, is the primary stimulator of Lipolysis. Epinephrine binds to specific receptors on the adipocyte, which in turn activates the HSL within the adipocyte itself. The Beta adrenergic receptors generally activate HSL and lipolysis, while the alpha adrenergic receptors have an inhibitory influence on LipoLysis. Once stimulated, HSL then activates Lipolysis and the breakdown of TG s into FFA s and glycerol which are then transported out of the adipocyte. Certain physiological conditions can amplify the adipocytes sensitivity to epinephrine. One very powerful amplifier of HSL-epinephrine is localized temperature. During aerobic exercise, HSL responsiveness to epinephrine is greatly enhanced due to an increase in body temperature and also due to in the increase blood concentration of epinephrine when compared to rest. This enhanced epinephrine-hsl sensitivity and effect in the presence of increased localized temperature is a very important mechanism in the success of LipoLite. Once the FFA molecules are transported out of the lipocyte and into the blood stream, they bind to albumin. Albumin is one of the blood proteins and the main transport vehicle for FFA. FFA molecules are not water soluble and therefore require a protein carrier to allow them to be transported to cells and within the blood stream. FFA s are transported to myocytes, where they are released from the albumin and carried across the muscle cell membrane by specific transporters. There are three main muscle cell transporters of FFA s, that facilitate the entry of FFA into the muscle cell: Fatty Acid Binding Protein (FABP), Fatty Acid Translocase (FAT) and Fatty Acid Transport Protein (FATP). These proteins bind the FFA molecules and transport them across the myocyte cell membrane to the mitochondria, where the FFA s undergo complete oxidation to produce the ATP energy needed for muscle activity. The other product of Lypolysis, glycerol, is called by lipoproteins to the liver for oxidation where it can be employed as an intermediary in the breakdown of glucose or used to make more TG s. 7

4 Lipoprotein Lipase Lipoprotein Lipase (LPL), is the second enzyme of Lipolysis. LPL is located on blood vessel walls throughout the body. Both adipose tissue and the liver have large quantities of this enzyme. LPL acts on TG s within lipoproteins in the blood stream. Lipoproteins are special blood proteins (LDL, VLDL and HDL) that carry cholesterol and TG s through the blood stream to fat storage depots (including the lipodystrophic LipoLite and Liposuction zones) and to the various cells in the body for energy. The TG s are broken down to FFA molecules and used as energy substrate by active tissues or are transported into fat and liver cells where they are re-synthesized into TG and stored as FAT. LPL is referred to as the gatekeeper that controls the distribution of TG in the various storage depots of the body. LipoLysis and the LipoLite procedure Clearly, to be successful, the LipoLite procedure must stimulate Lipolysis. Through Lipolysis, the triglyceride content of the adipocytes will diminish and, if the volume of lipolytic TG s reduction is sufficient, then there will be a discernible and pleasing contour alteration in the region of focal lipodystrophy that the LipoLite procedure had been treating. Epinephrine is the primary hormone that stimulates lipolysis. Epinephrine can bind to specific receptors on the adipocyte or myocyte and can either activate or inhibit HSL activity. The two main types of epinephrine receptors are the alpha and beta receptors. Epinephrine stimulates lipolysis by binding to beta receptors and can inhibit lipolysis by binding to the alpha receptors. Thus, it is the type of receptor that is available and its sensitivity to epinephrine that will determine the response of HSL in any given tissue and cell. Both alpha and beta receptors will be available on the same adipocyte, however, depending upon which receptor is more abundant and available for epinephrine binding determines the response of HSL and the resultant lipolysis cascade. There are certainly regional variations, as research has shown that the abdominal wall adipocytes are more sensitive to beta receptor stimulation by epinephrine than the hip and thigh adipocytes in both men and women. This research would suggest that abdominal fat is easier to mobilize with appropriate stimuli than that fat located in the hip and thigh regions. In addition to a relative beta receptor paucity in the thigh and hip adipocyte, these fat cells also tend to have a greater number of alpha receptors. A greater proportion of alpha receptors would favor the storage of triglycerides, as opposed to mobilization of TG s in the thigh and hip focal lipodystrophies. Women also tend to have a much higher concentration of LPL and activity in hips and thigh region compared to the abdomen. There also appears to be a correlation between the female hormone estrogen and TG mobilization and metabolism. Estrogen is felt to inhibit LPL, thus inhibiting the breakdown of TG in the blood stream and the subsequent storage in adipocytes. In addition, estrogen is felt to enhance epinephrine production and hence, HSL and its lipolytic effects on the adipocyte. Finally, the vasodilatory effect of estrogen may 8

5 increase blood flow and adipose perfusion, improving adipocyte epinephrine concentrations. Summary of LipoLytic Effects: Alpha Adrenergic receptors and stimulators: Beta Adrenergic receptors and stimulators: Inhibit lipolysis Promote lipolysis HSL -> LPL -> Stimulates lipolysis Promotes Lipogenesis, NOT lipolysis Epinephrine -> B receptors -> stimulates HSL -> lipolysis Heat (Vela) -> increases Epi -> B receptors -> increases HSL -> increases lipolysis CarboxyTherapy - > Anoxia -> epi -> B receptors-> HSL -> lipolysis -> vasodilation -> improved microcirculation -> Bohr effect -> increased p02 Mesotherapy PTC -> Phospholipid Membrane alterations -> 2nd messengers -> Lipolysis & Lipochalasis Aminophylline -> Beta receptors -> HSL -> Lipolysis Xylocaine -> vasodilation 9