posted June 14, 2000 10:20 PM            

Triglycerides and toggling the tummy

Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA. e-mail:
[email protected]

Multiple mechanisms regulate adipose mass and body weight. In addition to factors controlling appetite and energy expenditure, mechanisms controlling adipocyte number, triglyceride synthesis and triglyceride breakdown have important functions. But recent studies challenge our concepts concerning each of these.
It was only a few years ago that physiologists and physicians believed that the control of body weight was as simple as "you are what you eat". In short, weight gain in the form of increased body fat, leading to obesity, would occur when energy intake exceeded energy expenditure, whereas weight loss would occur when the converse was true. Energy intake, of course, represents eating, and was thought to be largely under control of the individual, with minor influence from external cues, such as the time of day and the availability and taste of food . Energy expenditure was also believed to be largely under the control of the individual through exercise and work, in addition to a small component referred to as the "basal metabolic rate", thought to be controlled mainly by the level of thyroid hormone in the blood.
Whereas the fundamental principle of energy balance represented by the first law of thermodynamics is still true, it has become clear that the mechanisms involved in the control of fat mass are extraordinarily complex . Appetite and energy expenditure are, in fact, highly regulated at many levels and by different regulatory mechanisms and feedback loops. It is now also clear that energy storage within the adipocyte can be regulated by the number and size of the adipocytes, the activity of the transcription factors that control adipocyte differentiation, and the lipases that are available to break down the stored triglyceride, the major form of energy stored in fat. Steven Smith and colleagues add more complexity to the regulation of fat mass by demonstrating that the acyl CoA:diacylglycerol transferase (DGAT), believed-until now-to uniquely control the one common step of synthesis of triglycerides in all tissues, is not the only protein to fulfil this function; mice deficient of the enzyme have a normal fat mass.
The most important control of adipose tissue mass in normal animals and humans is related to the balance between energy intake and energy expenditure. The need to have several mechanisms to regulate energy balance becomes evident on considering that the average human consumes between 800,000 and 1,000,000 calories per year (OS THAT ALL!!). If there were a consistent error as small as 1% in intake versus expenditure, one would store an extra 10,000 calories-about 3 pounds of fat-over the course of a year (I WISH IT WERE ONLY 3 lbs PER YEAR). Whereas regulation of appetite is dependent to some extent upon external cues, it must be highly regulated over the course of days, weeks and months; hence the need for the kind of robust 'super' system that is comprised by interconnected, highly regulated sub-systems. A brief review of the known molecular players provides a glimpse of the complexity inherent in weight control.
Coming to terms with complexity
Regulation of appetite is accomplished through a large number of peptides produced in both the brain and peripheral tissues. These appetite-regulating hormones can be divided into the orexigenic peptides that stimulate eating and the anorexigenic or anorectic peptides that inhibit eating. The former include neuropeptide Y, melanin-concentrating hormone, agouti-related peptide, galanin, and the orexins A and B. Appetite suppressants include leptin (a peptide expressed primarily in white fat tissue), -melanocyte-stimulating hormone, corticotropin-releasing hormone, cholecystokinin, glucagon-like peptide-1, neurotensin (LET'S GET SOME AND TRY IT) , and the cocaine- and amphetamine-regulated transcript (CART). The roles of many of these factors have been dramatically elucidated through the occurrence of natural mutations in both rodents and humans, as well as the creation of transgenic mice in which these hormones and their receptors have been either overexpressed or eliminated, respectively. For example, extreme obesity occurs in mice and humans with mutations in the genes encoding leptin, the leptin receptor and the melanocortin-4 receptor. On the other hand, mice that lack melanin-concentrating hormone tend to be thin and resist gaining weight.
Total energy expenditure is comprised of the energy used in exercise (unfortunately, only 10-20% in most of us), with the remainder represented by the basal metabolic rate and thermogenesis. In mammals, at least 20% of this is due to an 'energy leak' that occurs through movement of protons across the mitochondrial inner membrane of cells. This leak is largely regulated by a subgroup of the mitochondrial anion transporter superfamily comprising the uncoupling proteins (UCPs). *NB-THESE PROTEINS ARE THE TARGET OF DNP AND USNIC ACID*
There are three mammalian uncoupling proteins: UCP1, UCP2 and UCP3. Each is the product of a separate gene and has a unique tissue distribution. For many years the only known member of this family was UCP1, a protein that is expressed almost exclusively in mitochondria of brown fat tissue (the small pool of adipose tissue that is involved primarily in energy expenditure, rather than energy storage) and is highly regulated in its expression by thyroid hormone and adrenergic agents (*FOR INSTANCE EPHEDRINE AND CLENBUTEROL). Transgenic mice in which brown fat is eliminated become obese, but mice with inactivation of UCP1 are neither obese nor hyperphagic (OVER-EATERS), suggesting that other UCPs may compensate its deficiency. UCP3 is expressed in heart, brown and white adipose tissue and skeletal muscle, and is regulated in both lean and obese individuals undergoing fasting. Several polymorphisms (NATURAL GENETIC VARIATIONS) in this protein have been identified, and some are associated with severe obesity and type 2 diabetes. UCP2 is ubiquitously expressed, but the phenotype of the mutant mouse indicates that it may not have a significant influence in resting metabolic rate .
About the adipocyte
The final site of regulation of adipose tissue mass is the adipocyte itself. It has long been known that obesity may occur as a result of an increase in the number of adipocytes (hyperplasia), an increase in the amount of triglyceride stored in the adipocyte (that is, adipocyte hypertrophy), or a
combination of the two. Although adipocyte number has been traditionally viewed as being stable throughout most of life, it is probably a balance between the size of the precusor pool, the rate and extent of differentiation, and the rate of cell loss through apoptosis (DEATH). The rate and
extent of differentiation is controlled by a number of transcription factors, including SREBP-1, C/EBP and PPAR (SOME NUCLEAR PROTEINS). Several models of defects in adipocyte generation have been created in mice through the introduction of normal or dominant mutant variants of SREBP-1 or C/EBP, and two different variants of PPAR have been identified in humans and associated with obesity. With regard to the synthesis and breakdown of fat itself, the situation also used to be quite simple. Triglycerides are the major storage form of energy in adipocytes. Triglyceride synthesis depends on DGAT, a protein that catalyses the final unique step in the pathway to fat storage. As such, DGAT was thought to have a fundamental role in the physiologic processes involving triacylglycerol synthesis, such as the formation of adipose tissue, intestinal fat absorption, lipoprotein assembly and lactation. The Dgat-/- mice (MICE WITHOUT THE DGAT GENE) obtained by Smith , however, can still synthesize triglycerides and maintain a normal fat mass while on a regular diet. Curiously, they are resistant to dietary-induced obesity, but this is due to increased energy expenditure rather than a change in the rate of lipid synthesis. Although the site of increased energy expenditure has not been identified, this finding suggests that there may be another unrecognized link between triglyceride synthesis and regulation of the UCPs, perhaps at an intracellular level.

And so, as with other systems regulating body weight and fat mass, there must be at least two mechanisms to synthesize triglycerides in the mouse. This is paralleled by recent observations indicating redundant mechanisms for lipid breakdown. The genetic discoveries made over the past decade indicate that the regulation of adipose tissue mass is not as simple as we used to think-AND THAT STAYING THIN IS EVEN HARDER THAN IT USED TO BE.

posted June 15, 2000 12:32 PM            

Late

posted June 15, 2000 03:09 PM            

I don't think the brownfat decreases in size as much as it just doesn't function as well as we age. Although size of the brownfat pad is correlated with metabolic activity, but that seems to be under genetic control. What does change with age is the number of functioning mitochondria (our cute little energy factories), as well as other regulators of overall metabolism such as GH, Test, IGF and many other chemical messengers that inhibit or stimulate brownfat metabolism. As you can see, most of these messengers are targets of intervention to change the metabolic balance in our favor. Naturally these are the first choices for bodybuilders looking to get lean with a minimum of dieting and exercise.

I'll bet there's some clever biochemist/bodybuilder out there right now looking for ways to inhibit this DGAT protein. Artemis?

posted June 15, 2000 06:46 PM            

But Jaye, That IS my point! We do not even have the most basic map of the human DNA (yet!). Let alone what the function of each little �link� is, how each affects the body, and then figuring our how to manipulate them safely! If it�s one thing I�ve learned, there is never a silver bullet with dealing with the complex systems of the human body � or any living organism for that matter. So bring on the sucking machine and liberate me from my fat!

As a side note, this morning on the news, a report has found that one out of every two people in CA are now considered over weight. But as I look around in the office, I think they just might have called it low. It is truly a sad day.

Late

posted June 15, 2000 08:34 PM            

Do you know where the major auto manufacturers learned all of their tricks on performance enhancements? Shade Tree Motor Heads! It's the same with optimal nutrition. The academics are being driven by athletes. Sure we've made some mistakes over the years, but damned if we aren't superior at manipulating performance and metabolism. Yes Lobo, there are a lot of chemicals in there, but I'd argue that p/c/f manipulations alone compared to the 65/15/20 shit that society is growing on says more than the study printed above. Throw in your post on vitamins and minerals, and now we're setting a foundation upon which to test metabolism. Where the hell did they come up with 65% carbs in the first place?? Why the hell is everyone supposed to eat like a marathon runner with a history of heart disease?? Sound as much like halfassed propoganda to you as it does me?

You watch Lobo, I'm gonna get these hips to melt down without any more lipo and you will be in awe. Like the lady says, lipo just isn't a perfect solution. I think that you can influence hormones through diet in such a way to be more efficient than lipo. Unfortunately, it takes a little more decipline.

posted June 16, 2000 11:24 PM            

Late

Omega Lobo :p

posted June 19, 2000 01:16 AM            

Here's another one for Skydancer:
Loncar, D. Convertible adipose tissue in mice. Cell Tissue Res 1991; 266:149-161.

(many more references where these came from)

DNP itself becomes sort of an unregulated synthetic UCP. The benzene ring is hollow and lets the protons back across the mitochondrial membrane, while the other three substiutions hold it in place.

About the DGAT: does anyone know if this protein is specific to all fat-cells, or specific to only white fat cells?

Shall we talk about the effects of cortisol etc. besides thyroid etc. etc.

Lets keep this subject bumped. There seem to be many people applying no attention to macronutrient ratios at all who still stay lithe. This all gets so complicated...

Has anyone yet come up with Any study at all that demonstrated fat cells disappear from a depot without the surgery? I have been looking for a Long time.

posted June 19, 2000 02:25 PM            

Does sound drastic doesn't it? Trouble is though can anyone here (or anywhere else) offer any long term fat-loss sucess stories using just traditional diet&exercise? (Well, okay diet&exercise + supplements...)

When therapy stops, the fat cells refill.

Fat cells are difficult to count. Maybe a bulging area now has more fat cells in it than before when the area was thin? Could we prove/disprove this in a clinical setting?

posted June 19, 2000 03:50 PM            

And so far, the only fat-loss therapies that results in the fat staying off have been permanent lifestyle modifications. It is very rare for an obese person to make these changes permanent. I have a strong suspiscion this will always be the case for humans, no matter what drugs/genetic interventions science may come up with, I think they will still be short-term fixes or life-long drug therapy.

posted June 19, 2000 03:52 PM            

Are you working under the assumption that the number of fat cells, maybe in combination with genetic code necessarily determine the percentage of bodyfat any given person will gravitate towards under any circumstances? If so, then small permutations in environmental conditions would make small changes in %BF. If this is true, then yes, the only way is the elimination of the entire cell itself. In this assumption, you would be saying that no person ever substantially overweight manages long term weight loss.

Can we assume that overabundant fat storage only expands the size of given fat cells, or does someone have information suggesting that the body generates new/additional cells?

If the above assumption were true, then we would not be seeing the new development of overweight asian peoples exposed to western dietary habits. How do social disorders such as anorexia play into this theory?

I am at a loss in understanding what is happening at the molecular level when metabolism 'shuts down', and am new to the complexities of how and how many subsystems are involved in deciding when to store fuels and when to burn/metabolize. My success stories are invalid here given that I have had lipo surgery to address a genetic predisposition to large hips. But I do believe that those hips might not have become an issue had I not also been born moderately lame.

What do we know about the body's response/reprogramming as a result of removing some sum of fat cells. I can tell you that lipo was as dramatic as giving birth with respect to how the overall chemestry of my body changed. I can also tell you that I have had fat loss since the surgery as well. Did I change my genetic code? Maybe other subsystems are compensating for that loss? Honestly, I don't kow. But, I do believe that the BF% that I have lost over the last year+ has been a result of manipulating my diet and activity levels.

posted June 19, 2000 04:16 PM            

In support, I will concur that once an alcoholic, always an alcoholic...etc.
In contrast, I would argue that behavior modification does occur.

One of my clients right now is obese. This woman has been on various medications over the last ?10-15 years for depression, asthma, pain..etc. She came to me at 242(?) pounds. Now the pain meds are infrequent, the asthma meds are out of the picture and the prozac is out of the picture. She is down to 230-something on diet and strength development program. My trouble is getting her to eat enough: 4 meals for a composite 650 calories is not helping. She is actually very diciplined and dedicated. ...and thrilled with her new lifestyle.

posted June 19, 2000 05:24 PM            

We live in a society where cheap, yummy (ie high fat/sugar/salt) food is readily available and socially acceptable to eat. On top of this is bombardment by advertizers of these foods at a time when we are spending more and more time exposing ourselves to this advetizing as couch potatoes. The only ways an obese person can approach this problem is either by SHEER WILL POWER, which is almost impossible to sustain for life or by making major lifestyle changes. These changes take lots of time and effort. They include educating yourself about healthy food and exercize choices, and being in touch with your body enough to know what it really needs, not what it craves. It also includes 'swimming upstream' in society so that when you go out for a meal/wedding or vacation you don't feel social pressure to eat what everyone else is eating. It takes time to prepare or procure healthy meals so you are never at the mercy of fast-food merchants. And this is just the beginning. It requires support of friends and family, so that they are not stuffing their faces (in front of you) with french fries and whoppers while you're trying to develop a taste for fresh, raw veggies. Even harder is the mother who does all the cooking and shopping for the family but puts herself on a 'diet'. This is doomed to fail in the long run unless Mom can change her families eating habits. It is not impossible, and many people succeed, but most people do not succeed long-term.

I am not wishing this on your client. I hope she continues to lose the fat until she reaches her goal. But more importantly is I hope that by the time she goes on a maintenance diet she will have overcome most of these hurdles with your help.

Of course this does not mean that bodybuilders and other athletes can't use the science to help them with fat-loss. But as any competing bodybuilder will tell you, you can't stay 2%bf for life. It's a temporary, extreme diet. The opposite of what most of the population needs.