Brown adipose tissue

Once thought to be the holy grail of energy expenditure manipulators and a potential cure for obesity – fail.  I don’t have great evidence for this; it’s really just a hunch.

A new mouse study has provided some additional fodder for speculation, however.

The theory & background info: increased BAT activity can effortlessly burn away excess fat mass by using fuel to create heat instead of energy.  This model was most aptly summarized by the title of Dr. Efraim Racker’s 1963 ediorial: “Calories Don’t Count-If You Don’t Use Them.”  At best, I don’t think BAT is a panacea.  At worst, we might’ve learned our lesson long ago from DNP (circa 1938; also McFee et al., 2004; Miranda et al., 2006; Tewari et al., 2009; and Grundlingh et al., 2011).

drug banned

In a slurry of publications in 2009, researchers re-ignited the quest by showing cold-induced BAT activation in healthy humans (Virtanen et al., 2009):Virtanen BAT

Cold exposure, in this case, entailed  2 hours chillin at 64F, then alternating 5 minute bouts of placing one foot into a bucket of ice water (44F) – not wearing an ice pack on their upper back, as advocated by Tim Ferriss in The 4-Hour Body, or taking a cold bath as per Jack Kruse in his Cold Thermogenesis Protocol… although none of these interventions seem particularly comfortable.  The authors speculated the cold feet protocol could result in the loss of 9 pounds of fat mass over the course of a year.

Another study tested 2 hours at 61C in light clothing to a similar effect (van Marken Lichtenbelt et al., 2009):

Lichtenbelt BAT

Energy expenditure increased 5-30% upon cold exposure (that’s a lot).  They also showed that obese people had impaired BAT activity, although this is not entirely unexpected because they have more normal insulination (ie, adipose tissue), and therefore don’t require as much BAT activation to maintain thermoneutrality.

Nicotine can do this in rats, and even to a greater degree than ephedrine (Baba et al., 2007).  At least the former might be more tolerable than cold exposure and/or high dose stimulants.  Interestingly, however, 1 mg/kg ephedrine increases metabolic rate (+9%) more so than cold exposure (+5.5%; 2 hours wearing a 57F cold vest) but failed to activate BAT in humans (Cypess et al., 2012) – perhaps due to our relative lack of beta-3 receptors (?); although an earlier study estimated 19.5% of the 22%  increase in metabolic rate seen with 1 mg/kg ephedrine could be attributed to BAT (Astrup et al., 1985).

New mouse study: miR-155 kills BAT, and miR-155 KO mice have increased BAT (Chen et al., 2013).

Nomination for figure of the year (Richard Feynman might agree)?mIR155TG

Mice overexpressing mIR-155 (“mIR155TG”), the ones on the bottom, are chilly, suggesting reduced energy expenditure… so these critters should either be obese (they sure don’t look it) or at least not eating nearly as much to maintain normal body weight.  Nope:mIR155TG BW FI

They have much less BAT, but just as much fat.

What’s more interesting from the human obesity perspective is mice without miR-155, as I’m certain anti-miR155 is already in production for preclinical testing.  Indeed, and mice without miR-155 (miR-155-/-) are hot when it’s cold, ie, 39F:mIR155 KO

So these guys must be significantly leaner or eating massively to maintain a normal body weight…  baaaarely:mIR155 KO FI BW

Perhaps if they lived in a frosty tundra, miR-155-/- mice would reap the anti-obesity benefits of hyperactive BAT, but not much difference at room temperature.  Thus, if we were forced to live in frigid temperatures, naked, anti-miR-155 may keep us warm, but it might not be the cure for obesity living comfortably at room temperature.  I suspect that IRL, any effect of increased BAT activity would: 1) make us sweaty; and 2) be easily counterbalanced by increased food intake or reduced physical activity, the latter of which would at least help with all the sweating.

“Calories Don’t Count-If You Don’t Use Them”   huh?  Perhaps if by “Use,” Dr. Racker meant “Eat.”  Otherwise, I’m sticking with: the foods you eat are more important than their caloric content.  This is biology, not mathematics.

calories proper

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  • Nigel Kinbrum

    There ain’t no cure for the Kleiber’s law blues.
    “the foods you eat are more important than their caloric content. This is biology, not mathematics.”

    • William Lagakos

      Lol, “Kleiber’s Law Blues.” I like it.

  • George Henderson

    If extra energy output through BAT can be “easily counterbalanced by increased food intake or reduced physical activity”, why isn’t this true (or as true) of energy lost through ketogenesis?
    That is the $60,000 question.

    • William Lagakos

      Touchee, sir.

      I’ll take a guess: it is, at least partially – Garbow’s ketogenic mice tried to eat more to compensate but couldn’t quite do it (they still lost weight: In humans I’d bet something similar is going on – just like in type 1 diabetes.

      George, you’re making me re-evaluate my conclusion! Perhaps the wording “EASILY counterbalanced” is too strong. However, I suspect it would be easier to fully compensate on a mixed diet than on keto due to satiety, palatability, etc.

      all best,

    • Nigel Kinbrum

      May I take a stab?

      In humans, ketogenesis suppresses appetite and raises the level of hormones that can make people quite “lively”.

      In mice, low insulin greatly increases energy expenditure as heat, which is dissipated.

      In addition, when I feel cold, my appetite goes through the roof.

      • William Lagakos

        Nice summary. I imagine there might be a bit of overlap, and cold mice probably both eat more AND become more lively.

        • Nigel Kinbrum

          Becoming more lively doesn’t burn many more kcals in mice, due to their very low mass (~30g).

  • J D

    Good post Bill. ( Kindke here )

    I saw something similar back in this paper, gpr41 knockout mice had reduced energy expenditure but weighed the same as controls. Although the paper didnt report food intake of the mice, I dont expect the gpr41 knckout mice consumed less.

    There was a followup paper on gpr41 knockout showing increased obesity tendency but this was sex dependent.

    • William Lagakos

      Hi JD,

      Thanks for linking to the Kimura paper – they did such a comprehensive metabolic analysis, I’m really surprised they didn’t report food intake! It could’ve been an effect on motility, which would be in line with SCFAs as ligands; is this what you were thinking?

      … or it could’ve been a fluke: that follow up paper, by Bellahcene, showed increased BW due to reduced EE ( whereas Samuel showed decreased BW due to increased motility ( Bollixed :/


      • Nigel Kinbrum

        You need to leave a space between the end of a url and the “)” otherwise the link doesn’t work!

        • William Lagakos

          Thanks, Nigel!

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  • William Lagakos

    Whole-body cryostimulation as an effective method of reducing low-grade inflammation in obese men.

    3 minutes/session X 10 (once per day)
    SERIOUSLY COLD! -110C!!! in light clothing