Dietary protein affects lean weight gain, but not fat gain, during overeating

A January 2012 JAMA study reports that people eating 40% more calories than they expended for eight weeks gained the same amount of body fat regardless whether they ate protein at 5% (low protein), 15% (normal protein), or 25% (high protein) of calories.

But the amount of lean (muscle) weight gain (and thus total weight gain) and resting energy expenditure were influenced by the amount of protein eaten.

The weight gain in the low protein diet group was 3.16 kg, about half that of the other 2 groups (normal protein diet: 6.05 kg; high protein diet: 6.51 kg; P = .002). The rate of weight gain in the low protein diet group was significantly less than in the other 2 groups (P < .001). The failure to increase lean body mass in the low protein group accounted for their smaller weight gain [emphasis added]. …

Resting energy expenditure, total energy expenditure, and body protein did not increase during overfeeding with the low protein diet. In contrast, resting energy expenditure … and body protein (lean body mass) … increased significantly with the normal and high protein diets.

Weirdly, although all excess calories were fed as fat and were equal in all groups, and although all groups gained the same amount (3.51 kg) of body fat, the authors state that the low-protein group stored more than 90% of the extra calories as fat, while the normal- and high-protein diet groups stored about 50% of the excess calories as fat.

There were no significant differences between energy intake and energy expenditure between the 3 diets. We can account for all excess energy consumed through energy stored in fat and in protein or expended in higher total energy. With the low protein diet, more than 90% of the extra energy was stored as fat.

With the normal and high protein diets, only about 50% of the excess energy was stored as fat with most of the rest consumed (thermogenesis). The high total energy expenditure probably reflects the higher cost of protein turnover and storage.

What accounts for the increased energy expenditure in the normal- and high-protein groups? The work of building extra muscle mass.

Resting energy expenditure responded differently to low vs high protein intake. Neither resting energy expenditure, nor lean body mass increased in the low protein group. In contrast, the accretion of lean body mass in the normal and high protein groups was the principal contributor to the increase in resting energy expenditure [emphasis added].

Two important conclusions of this study:

Extra energy intake [calories] predicted both the increase in lean body mass and body fat. In contrast, protein intake predicted the increase in lean body mass, but not the change in fat storage.

Calories alone … contributed to the increase in body fat. In contrast, protein contributed to the changes in energy expenditure and lean body mass, but not to the increase in body fat.

Author George Bray, MD, talks about the study here:



Bray GA et al. Effect of Dietary Protein Content on Weight Gain, Energy Expenditure, and Body Composition During Overeating. JAMA. 2012;307(1):47-55. doi: 10.1001/jama.2011.1918

Saturated fat is good if carbs aren't too high

Eating saturated fat keeps appearing less harmful and more beneficial than previously thought.

A 2010 meta-analysis of prospective human studies found "that there is no significant evidence for concluding that dietary saturated fat is associated with an increased risk of CHD [coronary heart disease] or CVD [cardiovascular disease including stroke]."

And late last year, a University of Alabama study lent support to some paleo-like diets, higher in saturated fats and low to moderate in carbohydrates.

The study indicates that eating more saturated fat (found in meats, butter, and coconut oil) may lower one's serum triglycerides (TG) and cholesterol on very low-density lipoprotein (VLDL-C), but only if one keeps carbohydrate intake at or below around 50% of calories.

Lower VLDL-C and TG are associated with a reduced risk of heart disease.

This beneficial effect of saturated fat was seen when people ate more than 12% of calories (energy) as saturated fat.

Eating more than 50% of calories as carbohydrate made the good effect of saturated fat disappear, however.

Studies that fail to account for the interaction between dietary carbohydrate and saturated fat apparently mask this link to VLDL-C and TG.

Wood AC, et al. Dietary Carbohydrate Modifies the Inverse Association Between Saturated Fat Intake and Cholesterol on Very Low-Density Lipoproteins. Lipid Insights 2011 August 23; 2011(4): 7–15.

(from protein.md)

Keep eating, say fat people’s brains

More on the topic of brain changes in obesity:

An April 2011 Nature article by French researchers demonstrated that diet-induced obesity in miniature pigs leads to decreased activation of the prefrontal cortex, a brain region used for “inhibition of inappropriate behavior, satiety, and meal termination.”  The brain activation was determined by regional blood flow as measured by SPECT imaging.

Like the pigs, obese men also show reduced activation of their prefrontal cortex, and it’s not known whether these brain changes cause obesity, or obesity causes the brain changes.

Either way, less neural activation of this brain region may at least partly explain why fat people find it hard to put the fork down.

This paper concludes that “reduced activation of prefrontal cortex observed in obese humans is probably an acquired feature of obesity since it is also found in minipigs with a diet-induced obesity” (emphasis added).

If diet-induced obesity indeed causes reduced prefrontal cortex activation, then this may lead to a vicious cycle: one’s diet causes weight gain, which diminishes one’s brain signaling to stop eating, leading to more food intake and weight gain, causing further reduced brain signaling, and so forth.

Here’s the abstract:

Compared to lean subjects, obese men have less activation in the dorsolateral prefrontal cortex, a brain area implicated in the inhibition of inappropriate behavior, satiety, and meal termination. Whether this deficit precedes weight gain or is an acquired feature of obesity remains unknown. An adult animal model of obesity may provide insight to this question since brain imaging can be performed in lean vs. obese conditions in a controlled study. Seven diet-induced obese adult minipigs were compared to nine lean adult minipigs housed in the same conditions. Brain activation after an overnight fasting was mapped in lean and obese subjects by single photon emission computed tomography. Cerebral blood flow, a marker of brain activity, was measured in isoflurane-anesthetized animals after the intravenous injection of 99mTc-HMPAO (750 MBq). Statistical analysis was performed using statistical parametric mapping (SPM) software and cerebral blood flow differences were determined using co-registered T1 magnetic resonance imaging (MRI) and histological atlases. Deactivations were observed in the dorsolateral and anterior prefrontal cortices in obese compared to lean subjects. They were also observed in several other structures, including the ventral tegmental area, the nucleus accumbens, and nucleus pontis. On the contrary, activations were found in four different regions, including the ventral posterior nucleus of the thalamus and middle temporal gyrus. Moreover, the anterior and dorsolateral prefrontal cortices as well as the insular cortex activity was negatively associated with the body weight. We suggested that the reduced activation of prefrontal cortex observed in obese humans is probably an acquired feature of obesity since it is also found in minipigs with a diet-induced obesity.

Val-Laillet D, et al. Changes in Brain Activity After a Diet-Induced Obesity. Obesity 19, 749-756 (April 2011).

Being fat suppresses brain cell formation

A new study from Harvard Medical School provides more evidence that diet-induced obesity hurts the hypothalamus, the brain region that drives your body’s energy usage and eating behavior.

As discussed here previously, a December 2011 University of Washington study showed that the hypothalamus in fat people is harmed by gliosis, a process leading to scarring.

This damage is possibly due to inflammation caused by eating a diet containing excess fat and/or energy (calories). Rodents develop this brain damage after being fed a high-fat diet, so causation by diet appears certain, at least for mice and rats, if not humans.

The Harvard researchers found that obesity in mice, whether due to a high-fat diet or leptin deficiency, also reduces neurogenesis (formation of new neurons) in the hypothalamus.

Ordinarily in adult mice, and perhaps humans, there is turnover of neurons (nerve cells) in the hypothalamus: new cells form, and old cells die. This keeps the hypothalamus “young,” working well in controlling body weight.

How do new neurons arise? Stem cells in the hypothalamus differentiate into progenitor cells, which, through cell division, become more mature, eventually producing new neurons.

A simplified view of the multistep process leading to generation of neurons is that slowly proliferating multipotent stem cells give rise to highly proliferative progenitor cells that have limited capacity for self-renewal (neuroblasts) and ultimately give rise to neurons.

Study findings

1) Compared with chow-fed (control) mice, the mice fed a high-fat diet showed less neurogenesis in the hypothalamus, making fewer new neurons and retaining more old ones.

DIO [diet-induced obesity] leads to an expansion of the pool of hypothalamic neural stem-like cells while leading to a depletion of the pool of highly proliferative progenitor-like cells. This suggests that DIO inhibits the differentiation of stem-like cells into more proliferative progenitor-like cells and/or impairs the survival of these progenitor-like cells.

2) Leptin-deficient mice, which become fat because there’s not enough leptin around to tell their brains to stop eating after a meal, ”also generated fewer new neurons, an observation that was explained in part by a loss of hypothalamic neural stem cells,” said the study’s authors.

Rescue by food restriction

The good news is that short-term calorie restriction rescues the neurogenesis that has been impaired by diet-induced obesity.

When the diet-induced obese mice were calorie restricted for four weeks to 70% of the intake of control mice, their body weight fell to similar levels as those of the control mice.

More importantly, calorie restriction restored the mice’s ability to grow form new hypothalamic neurons.

[T]he number of hypothalamic … neural stem-like cells [] was similar to that obtained with DIO control mice. In contrast, the number of actively proliferating progenitor-like cells was increased by 69% after calorie restriction ….

This may bode well for fat people who restrict calories.

It would be interesting to see what the effect of calorie restriction is, if any, on the degree of hypothalamic MRI abnormalities seen in humans in the University of Washington study.

In obese mice, the UW researchers found clear evidence of neuron loss and irreversible gliosis, i.e., scarring, in the hypothalamus. This damage was seen under the microscope and by immunohistochemistry.

In obese humans, the UW researchers found that part of the hypothalamus exhibited a mildly hyperintense T2-weighted signal, which indicates gliosis in these patients. But in theory, this finding could also represent at least a component of reversible edema (increased water content) due to inflammation.

If there is a reversible component to this hypothalamic damage in humans, we can hope that some treatment, such as calorie restriction, may partially reverse the damage.

Fat people are brain damaged

Unfortunately, many, if not all, obese people are brain damaged.

The damage, detectable by brain MRI, is subtle but potentially significant, sort of like that done by punches to boxers’ heads.

University of Washington researchers revealed in a new paper, co-authored by Stephan Guyenet, that obesity in mice, rats, and humans is associated with, and may in at least some cases be caused by, inflammation and gliosis (scarring) in the brain region that controls eating and body weight, the hypothalamus.

Here’s the paper’s abstract:

Rodent models of obesity induced by consuming high-fat diet (HFD) are characterized by inflammation both in peripheral tissues and in hypothalamic areas critical for energy homeostasis. Here we report that unlike inflammation in peripheral tissues, which develops as a consequence of obesity, hypothalamic inflammatory signaling was evident in both rats and mice within 1 to 3 days of HFD onset, prior to substantial weight gain. Furthermore, both reactive gliosis and markers suggestive of neuron injury were evident in the hypothalamic arcuate nucleus of rats and mice within the first week of HFD feeding. Although these responses temporarily subsided, suggesting that neuroprotective mechanisms may initially limit the damage, with continued HFD feeding, inflammation and gliosis returned permanently to the mediobasal hypothalamus. Consistent with these data in rodents, we found evidence of increased gliosis in the mediobasal hypothalamus of obese humans, as assessed by MRI. These findings collectively suggest that, in both humans and rodent models, obesity is associated with neuronal injury in a brain area crucial for body weight control.

And from the paper’s interesting discussion:

[W]e report that hypothalamic inflammation induced by HFD feeding is a manifestation of neuron injury that in turn triggers a reactive gliosis involving both microglial and astroglial cell populations. Moreover, these responses appear to occur selectively in the ARC and rapidly follow the initiation of a HFD. The transient nature of this hypothalamic response suggests that neuroprotective responses are mounted that limit or reverse the injury during its initial phases, but, with sustained exposure to the HFD, ARC-ME gliosis and injury responses are reestablished. Combined with MRI-based evidence for gliosis in the MBH of obese humans, our findings suggest that, in both humans and rodent DIO models, obesity is associated with neuron injury in a brain area crucial for body weight control. …

[I]n rats and mice that are susceptible to [diet-induced obesity], consumption of a HFD rapidly induces neuron injury in a brain area critical for energy homeostasis. Although local responses appear to limit this injury, recovery is transient, eventually giving way to chronic inflammation, neuron loss, and reactive gliosis. Extending these findings is MRI evidence for gliosis in the hypothalamus of obese humans. Collectively, this work identifies a potential link between obesity and hypothalamic injury in humans as well as animal models.

In this study, the high-fat diet (Research Diets D12492) fed to the rodents that developed hypothalamic injury contained, by calories, 60% fat (10:1 ratio of lard to soybean oil), 20% carbohydrate, and 20% protein.

So at least in rodents, a sustained, freely eaten high-fat diet – which is also hypercaloric, producing weight gain – leads to injury and death of brain neurons. This in turn produces scarring there, followed by obesity.

MRI images show that the same sort of hypothalamic scarring induced by a sustained high-fat diet in rodents also exists in obese people! The heavier the person, the more brain scarring there is.

This makes sense as a causal mechanism. Some people’s brains may be injured by chronically eating a diet that is high in calories and/or fat. (It’s unclear from this study whether carbohydrates or protein play any role.) As neurons in the hypothalamus — a brain region involved in controlling appetite, satiety, and energy expenditure — become inflamed and then die, these people gain excess weight and find it very hard to lose.

Perhaps this explains obese people’s leptin resistance, which makes their brains ignore leptin’s signal to stop eating once they’ve consumed enough food. Indeed, brain inflammation has been shown to create the leptin resistance seen in fat mice.

In rodent models of diet-induced obesity (DIO), increased inflammatory signaling in the mediobasal hypothalamus (MBH) similarly contributes to leptin resistance and weight gain.

Thaler JP, et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest. 2011; doi:10.1172/JCI59660.

Postscript: Dr. Guyenet discusses here another role of inflammation in obesity: producing insulin resistance. He notes, “Energy excess causes inflammation, and inflammation causes insulin resistance.”

( more at http://protein.md )

Welcome to Protein.MD

Hello everyone, 

This is the first post for Protein.MD, a blog focusing on diet’s influence on health and aging. Research in this field is exciting and has grown enormously in recent years.

The main address for this blog is http://protein.md

I’m busy with work these days, but intend to blog when I can. I’m also penning a book on this subject when I find spare time.