Another interesting read
There's a lot of anecdotal evidence that low-carbohydrate diets have a metabolic advantage, i.e .that a person on a low-carbohydrate diet can eat more calories than one on a low-fat diet and as a result not put on body fat but feel warmer and more energetic. However, I personally haven't seen any research that might elucidate the biochemical cause for such a result.
Normally in a high-carbohydrate diet, body fat composition is regulated by insulin. Insulin is excreted by the pancreas in response to hightened blood glucose levels, and in turn insulin causes muscle and fat tissue to absorb glucose from the blood stream. Eventually tissues become glucose saturated and hence are said to be insulin resistent. Insulin resistance (aka metabolic syndrome) is associated with many of the so-called 'Diseases of civilization.' See my review of Gary Taubes' book, "Good Calories, Bad Calories" for an overview of this set of hypotheses.
However, something has to regulate the volume of fat cells in the total absence of carbohydrate in the diet. Now protein intake does influence insulin levels too but something prevents individuals on a zero-carbohydrate diet from completely zeroing their body fat levels. One possible source for uptake of fatty acids into actual fat (adipose) tissue is a molecule known as Acylation-Stimulating Protein (ASP, also sometimes known as Acylation-Stimulating Peptide) .
The regulation of fat metabolism is really quite complicated compared to glucose metabolism. Suffice it to say, in vitro studies of fat cells in culture has shown that ASP is of great importance in determining whether fat cells allow lipoproteins to enter them or not. Lipoproteins are the so called blood cholesterals (LDL, HDL, triglycerides) that transport fats through the circulatory system.
There is some debate as to the body-wide (endocrine) importance of ASP. To phrase it another way, while there's a lot of evidence that ASP is the immediate cause of uptake of lipids into fat tissue, it's not clear if it is the proximate cause. The problem is, we lack an understanding of precisely what regulates ASP production in an organism.
To try and answer this question, I started with a 2003 review of ASP from K. Cianflone, who appears to be the leader in the field of ASP metabolism:
Edit:KO mice are those who are unable to produce ASP or have the gene permanently switched-off/down-regulated. This is a heavily loaded statement that deserves further investigation. It strongly suggests there are situations for a warm-blooded mammal where caloric intake has little correlation to the total volume of fat tissue. Furthermore, later in the review there is the statement,Finally, the most intriguing finding was that although the KO mice were leaner, food intake was much greater (up to 18% more caloric intake) with a normal fat absorption [85], raising the question: Where does all this energy go? How does the lack of ASP result in repartitioning and disposal of excess energy? The balance of body energetics would predict that any calories ingested, and not stored in some form, would have to be expended as energy. The major options are increased activity or enhanced thermogenesis. Preliminary results presented at a recent meeting (late breaking abstract, NAASO 2001) demonstrated increased oxygen consumption in KO mice, but no changes in overall activity, suggesting alternate disposal routes in the absence of efficient adipose tissue storage.
The final paragraph is particularly interesting, although somewhat vague. C3 is the precursor to ASP. We can make two critical assertions from these quotations, however:With the many factors that change postprandially or in insulin-resistant states such as diabetes, it is difficult to pinpoint exactly which component might be responsible for the stimulation of C3 and ASP production. Experiments with cultured human adipocytes have demonstrated that insulin (to a moderate degree), but especially chylomicrons, appear to stimulate both C3 and ASP production [44, 45 and 46]. On the other hand, Koistinen et al. [39] showed that a euglycemic (4 h) hyperinsulinemic clamp had no effect on C3 mRNA levels. C3 mRNA did correlate with BMI, glucose disposal rate, plasma triglyceride, non-esterified fatty acid (NEFA) and leptin (n=12 subjects) [39]. We speculate, therefore, that ASP production may be up-regulated in insulin-resistant states, perhaps by one of the factors listed above.
A recent article demonstrated that diets containing differing types of fat (polyunsaturated vs. trans fatty acids) have been shown to influence fasting ASP levels after several weeks feeding in hypercholesterolemic women [47].
- 1. Down regulation of the gene expression that regulates ASP production results in an organism consuming and expanding more calories than it normally should at the expense of accumulating fat.
2. Diet influences ASP production.
The question we really want to know is, what vector down-regulates the production of ASP? I went digging for an update on quote #1, and found the following, "Intestinally derived lipids: Metabolic regulation and consequences—An overview,"
Notes to the reader: NEFA is non-esterified fatty acids, hyperphagia is increased appetite (and nothing more in this context). C5L2 is some receptor that determines gene expression (and hence production of the mRNA that controls the cellular machinery). Ok, so regulation of C5L2 is the key now, but what drives that?Recent evidence in knockout (KO) ASP deficient (C3 KO) and C5L2 knockout (C5L2 KO) mice studies highlight the role of ASP and its receptor C5L2 as a peripheral gatekeeper. As C3 is the precursor to ASP, C3 KO mice are obligate ASP deficient. Initial studies [41] and [42] clearly demonstrated that the absence of ASP led to postprandial lipemia, while acute ASP injection normalized the response. Factor B KO mice, which have circulating C3 but under normal unstressed conditions have no circulating ASP, also demonstrate a similar profile [43]. Interestingly, the absence of ASP also leads to a reduction in storage within adipose tissue. The recent identification of C5L2 as a receptor for ASP [30] and [31], and the acquisition of C5L2 KO mice, has permitted further confirmation. C5L2 KO mice demonstrate similar delays in postprandial TG and NEFA clearance, with a marked reduction in ex vivo adipose tissue lipogenesis, absence of ASP stimulation and increased basal lipolysis [44]. Notwithstanding the apparent decrease in adipose storage, all KO models examined (C3 KO, factor B KO, C5L2 KO and ob/ob C3(−/−) double KO) demonstrate mild or marked hyperphagia [41], [42], [44], [45], [46] and [47].
Lipid flux, and thus LPL, is controlled by events within the adipocyte. In the absence of ASP, where does the energy go? ASP deficient mice and C5L2 KO mice have increased basal and food-induced thermogenesis, as well as mild to marked increase in physical activity in ASP KO mice [44] and [45] Z. Xia, K.L. Stanhope and E. Digitale et al., Acylation-stimulating protein (ASP)/complement C3adesArg deficiency results in increased energy expenditure in mice, J Biol Chem 279 (2004), pp. 4051–4057. View Record in Scopus | Cited By in Scopus (24)[45]. In fact, this increase in energy expenditure can partially reverse the decreased energy expenditure and insulin resistance associated with leptin deficiency [46]. Brown adipose tissue does not appear to contribute to the increased energy expenditure [45]. Interestingly, there is increased flux of NEFA to muscle and liver, with increased lipid oxidation, and overall increases in energy expenditure as compensation. Recent data indicates that this up-regulation is due to increased mitochondrial activity reflected by increased markers including CD36 and cytochrome C [47]. As C5L2 is also expressed in muscle and liver, whether this effect is a direct consequence of the absence of ASP or the result of increased fatty acid fluxes remains to be determined.
I did a little more digging, and found:
The ASP receptor C5L2 is regulated by metabolic hormones associated with insulin resistance (pdf)
Nuts! (hat-tip General McAuliffe.) Did we just take this journey through Cianflone's research to prove that acylation-stimulating protein, the primary effector of the uptake of fatty acids into fat tissue, is regulated by insulin!?! We also need to know what dexamethasone is, of course, but this is a key result.In preadipocytes, insulin and dexamethasone increased C5L2 mRNA (1 micromol/L insulin resulted in a 2.6-fold increase...
I guess the insulin-carbohydrate hypothesis of obesity still holds. We now have a fairly strong hypothesis as to the origin of the increased energy people report from low-carbohydrate diets. However there's also some evidence from the impact of steroids on ASP production that stress and inflammation also has a direct impact on body composition. Thus the absolute minimum body fat composition (~ 5 %) that an organism can maintain would appear to be a function of both insulin production from protein and baseline sex hormone levels. Exploration of that statement will have to wait for another time, another blog post.
