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Perilipin:

A Potentially Controllable Obesity Gene

Dr. Ralph Ofcarcik, Ph.D.
Red Mountain Spa Director of Nutrition Services

We’ve all known heavy families - clans where obesity rules. Mom, dad - both heavy; ditto for the kids. Occasionally, a lean offspring may surface, usually a male, much to the chagrin of his weight-conscious siblings. Although a lone, thin exerciser in a clan of couch potatoes may keep excess body weight at bay by lifestyle, there are individuals – Lazy Boy and dessert-loving people – who will look the same at 40 as they did at their high school graduations. Not fair!

Obviously, genetic expression in support of weight gain or control can impact our health, certainly our appearance. And, according to scientists investigating body fat at the cellular level, our genes play a much bigger role in the current obesity epidemic than previously thought. Weighting the compounding effect of thousands of metabolic factors, some inroads have been made into the genetic regulation of exercise aversion (“couch potato gene”) and appetite suppression (“stop-eating gene”). As yet, no single gene has earned the coveted(?) title of “thee obesity gene”. This may change, however, as we learn more about the perilipin gene, a genetic inducer of a fat globule shielding that fiercely dampens lypolysis. Less lypolysis = less fat burned for energy = greater retention of body fat.

Credit for the discovery of perilipin goes to Dr. Andrew Greenberg who, in 1991, discovered the new protein while serving a fellowship with N.I.H. After Greenberg later joined the Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) in 1993, his laboratory became the unchallenged leader in the perilipin research. When first discovered, perilipin was found to surround fat stores in fat cells and was intuitively (and correctly) regarded as an important entity in fat metabolism with specific function(s) yet to be determined. Currently, it is regarded as a major genetically influencing obesity promoter.

Whether we have a genetic tendency to be super models or super-sized depends – to a large part - on how efficient we are at utilizing body fat for energy. Stage 1 of the process begins when systemic lipases (fat breakdown enzymes) enter our fat cells. Once inside the fat cell, lipase enzymes will attempt to infiltrate the oily fat droplet to begin lypolysis. Only the gatekeeper (perilipin) stands in their way. Perilipin is not unlike a protective proteinaceous blanket that surrounds the droplet, warding off lipases and other enzymes. Since the amount of perilipin varies between individuals, those with “thin blankets” recognize a much greater infiltration of lipase enzymes into the fat store. The result: shock and awe – greater lypolysis, efficient use of fat for energy, and a tendency toward leanness. To the contrary, those with thicker coatings tend to retain body fat, may dampen daily caloric output, and will rely more on carbohydrate (glucose, glycogen) and protein (muscle, circulating aminos) for energy.

Early research demonstrating perilipin’s role in body fat retention was conducted on rodents by Baylor University investigators. Compared to controls, sedentary mice bred to have no perilipin in their fat cells had 8% more lean body tissue, little body fat, ate 25% more calories, and had significantly higher basal metabolism1.

With subsequent studies of human DNA, scientists found 4 variations of the perilipin gene, two of which promote greater body weight via increased perilipin synthesis. In a Tuft’s study of a 734 Caucasian participants, women with the two fat-promoting variants had significantly higher percent body fats, waist measurements, and body-mass indices. The same pattern was not found in men, likely because of hormonal differences. Currently, the two inherited perilipin-promoting alleles are regarded as a significant marker of obesity in women2. Interestingly, the other two variations (leanness-promoting) have been linked to reduced risk of diabetes in both women and men (Amish Family Diabetes Study) 3.

Since the risk of obesity (women) and diabetes (women, men) increases in the presence of elevated perilipin, what can we do keep it at minimal levels? Researchers tell us that we may be within a few years of developing medications or dietary constraints that will suppress expression of the two obesity-promoting variants. However, a few post-translation strategies currently exist and may work. Consider:

Magnolol is a component of magnolia bark, a supplement used in Japan for centuries for “anxious eating”. It is also said to be a lucrative source of perilipin inhibitors. In 2000, Chinese researchers demonstrated that magnolol significantly reduced lipid droplets in adipose tissue4. No safety or contraindications have been noted, other than slight drowsiness. Typical dosage recommendations are for a magnolia bark decoction (hot-water extract as with a tea) using 3-9 grams of dried bark. Modern-day usage is most often in powdered or pill form, in which case the daily dose ranges from 250-750 mg/ per day of an extract standardized for the primary active ingredients (typically 1-2 percent magnolol and honokiol).

Myriceline™ is commercial anti-cellulite product produced from bayberry and manufactured by Centerchem, Inc., a 58-year-old specialty ingredients company located in Norwalk, CT. Its efficacy is said to be premised upon several functions, one of which is the phosphorylation and subsequent removal of perilipin from fat globules. More information can be obtained at the website, i.e. www.centerchem.com.

Other animal studies have demonstrated a dramatic blunting of perilipin degradation by the introduction of fatty acids. Theoretically (and far from conclusive), it is at least feasible to hypothesize that low-fat diets may be the nutrition therapy of choice for those who test positive for amplified perilipin transcription.

Studies Cited

1. Saha P, Kojima H, Martinez-Botas J, Sunehag AL, Chan L. 2004. Metabolic adaptations in the absence of perilipin: Increased oxidation and decreased hepatic glucose production associated with peripheral insulin resistance but normal glucose tolerance in perilipin-null mice. J Biol Chem 279:35150-35158.

2. Acton S, Osgood D, Donoghue M, Corella D, Pocovi M, Cenarro A, Mozas P, Keilty J, Squazzo S, Woolf EA, Ordovas JM. 1999. Association of polymorphisms at the SR-BI gene locus with plasma lipid levels and body mass index in a white population . Arterioscler Thrombosis Vasc Biol 19:1734-43.

3. Damcott C, Laurie J, Reinhart L, Shi Jian Wang X, O’Connell J, Braxton D, Mitchell, B, fried S, Greenberg A, Shuldiner A. 2005. Genetic variation in perilipin is associated with lower risk for type 2 diabetes and obesity in the Old Order Amish. Presented at the 2005 Meeting of the American Diabetes Association.

4. Seu-Mei Wang S, Lee L, Huang Y, Chen J, Chen Y. 2000. Magnolol stimulates steroidogenesis in rat adrenal cells. British Journal of Pharmacology 131, 1172-1178.