Calorie restriction for weight loss?

I am strongly against calorie restriction. All the evidence I have seen indicates that, even if weight loss does occur, it changes your physiology and sets you up for future weight gain. Heres an introduction to "wet your appetite".

If an animal is in energy balance, its body mass and body composition generally remain stable. Although animals can adjust for subtle alterations in energy budget over the short term, prolonged imbalances can cause weight gain or loss. Dietary restriction has been advocated as a treatment for obesity for over 2500 years (Hippocrates, 5th century B.C.). Yet, despite the fact that caloric restriction is the oldest, most frequently prescribed and self-prescribed treatment for overweight and obesity, the strategy is seldom successful. Rates of weight loss under restriction are rarely sustained for any protracted period. Moreover, the lost weight is frequently regained when the period of restriction ends. ( link )

This paper does a good job of laying out what happens with calorie restriction, here are the best bits.....

• There are 3 primary mechanisms how organisms cope with reduced calorie intake, increased digestive efficiency, reduced basal metabolic rate, and third, reduced activity.
• There are 2 phases to calorie restriction, first, an adaption phase, where energy parameters are adjusting ( reducing ) to match the new energy availability of the diet. And second, a maintenance phase where the adjustments are now complete and energy balance is established. ( i.e. weight loss has finished, you are now weight stable at a reduced calorie intake, welcome to hypo-metabolism )
• Body temperature declines during calorie restriction, shown for both rodents and monkeys.
• During calorie restriction, not all weight lost is fat mass, a significant amount is also fat-free mass.
• Different things happen depending on the severity of the calorie restriction. For example in rats, 25% reduction allowed only temporary weight loss before compensatory mechanisms adapted and body mass increased again. Meanwhile 50% reduction wasn't able to be compensated for and body mass continued to decline.
• In Monkeys, After 30% calorie restriction for 5 years only fat-free mass showed reductions, fat mass was comparable to controls.

And lets not forget our 5% calorie restricted mice that straight out gain fat mass. In general it appears mild calorie restriction serves only to increase fat mass.

A recent study has examined the neuroendocrine changes that occur with diet-induced weight loss. ( Lets put aside the well known affect of leptin insufficiency for the moment ). One of the things that occurs in diet-induced obesity is ghrelin resistance in the AgRP neurons. Normally, ghrelin serves to increase AgRP.

So anyway, this study starts off with making some rodents fat, ( high-fat diet again ) then, after obesity is established, they switch the diet of the rodents back to chow, or chow with 40% calorie restriction. Heres a graph of the final body weights...

Both sets of rodents switched back to chow and chow with 40% calorie restriction lost weight. The calorie restriction group lost more weight than the Ad libitum chow group. Although this just barely made statistical significance. This is 40% calorie restriction btw, if you live on 2000 calories per day this is equivalent to putting you on a diet of 1200 calories per day, and you loosing only slightly more weight than someone eating 2000 calories per day.  Sounds fair right?

Now here is the really interesting part, despite both the chow and chow + 40% calorie restricted groups both losing weight, ONLY the 40% calorie restricted group experienced a ( very ) significant increase in hypothalamic AgRP expression. See next graph.....

Despite the 40% calorie restricted group weighing the same as never obese controls, they have marked increased AgRP. Hence, just because they weigh the same as controls, they are NOT metabolically the same as controls. The increased AgRP means their bodies perceive their current weight to be too low and in a state of starvation even though they are actually of normal weight.

But look at HF-C, this is the group that lost weight eating Ad Libitum. They had the same level of AgRP as controls, indicating that their bodies did not perceive their new reduced weight as a state of starvation. This result suggests that weight loss without enforced calorie restriction does not increase AgRP, and so should hopefully make you less vulnerable to weight regain. Indeed, the authors make the point that it is the detection of negative energy balance that leads to increased AgRP following weight loss, and not the actual weight loss itself. If you can lose weight without your body detecting the negative energy balance, without stimulating an increase in AgRP, your probably more likely to maintain the weight loss.

In short, this study says weight loss must be achieved without enforced calorie restriction to be sustainable. Weight loss with enforced calorie restriction increases AgRP, which is NOT sustainable unless you prefer to live in misery.

Infact we saw this same thing back in the ketogenic diet unique state study.  Mice subjected to 35% calorie restriction had a nasty increase in AgRP despite similar bodyweight compared to ketogenic fed mice eating Ad Lib. Although these mice did not start off from an obese state.

This increase in AgRP in response to calorie restriction is very prominent in the literature, and make no mistake, AgRP WILL make you gain weight.

Lets re-iterate how potent AgRP is, courtesy of this paper.

• Agouti-related protein acts as an inverse agonist for the melanocortin receptors, MC3R/MC4R
• The integral role of the melanocortin system in body weight homeostasis is supported by the fact that any mutation in the melanocortin signaling pathway including MC3R- or MC4R-null mutants and ectopic expression of MCR3/4 antagonist, AgRP, results in hyperphagia, hypometabolism, hyperinsulinemia, and hyperglycemia in both rodents and humans
• The release of α-MSH by POMC neurons and its binding to G-coupled MCR’s initiates the central anorexic signaling pathway that results in decreased food intake and increased energy expenditure while AgRP exerts its orexigenic action partly by blocking the binding of α-MSH to its receptor there by preventing the α-MSH-induced anorexic pathway
• Thyroid-releasing hormone (TRH)-, oxytocin (OT)-, and corticotropin-releasing hormone (CRH)-expressing neurons located in the PVN all express MC4R. The binding of α-MSH to MC4R on these neurons has a positive action onto the hypothalamic–pituitary–thyroid (HPT) axis and the hypothalamic–corticotropic axis (HPA). During fasting ( or calorie restriction as we learned in this post ), increased release of AgRP by AgRP neurons has been demonstrated to be a key mechanism for fasting-induced down regulation of the HPT axis and the consequent adaptation during negative energy balance
• AgRP neurons are necessary and sufficient to initiate the full feeding sequence.
• extinction of α-MSH signaling cascade was not necessary for AgRP neurons to initiate feeding. ( basically this is saying an increase in AgRP will always initiate feeding, regardless of what the POMC neurons are doing )
• Lack of AgRP neurons results in death from starvation because mice lose all interest in food and stop eating.
• AgRP decreases fertility ( link )
• AgRP increases respiratory quotient, making you oxidize carbohydrate and preserve fat. ( link ) 

"Starvation mode" is a mythical bro-science term that would commonly be stated to be a mode that you get into if you chronically restrict food intake. Well to me, it looks like "starvation mode" is actually a very real phenomenon and is mediated by AgRP.