to the editor: We thank Ollie Jay and David Raubenheimer (3) for their interest in our paper (2) and in the issue of possible extrapolations of our studies to human metabolism. We find little difference between their opinions and our conclusions.
We agree that there may be issues to be discussed in extrapolating mouse data to human conditions. Importantly, and irrespective of any of our results, there is a substantial difference metabolically between mouse and human daily life. Experimental mice are normally chronically cold exposed (≈20°C) day and night, whereas humans strive to constantly remain at thermoneutrality and are successful in doing this most of the time. Therefore, any increased insulation would result in decreased heat loss in the mouse, leaving more of the energy of the food intake to be accumulated; in humans there are no physical reasons to think that changes in insulation would affect metabolism, since normally little of our metabolism is used in heat loss defense.
In our opinion, there can be no such thing as thermogenesis “activated at the cooler end of thermoneutrality;” the lowest temperature that is thermoneutral is the one below which extra thermogenesis is activated, but when this happens we are no longer at thermoneutrality. Any temperature that causes an increase in metabolic rate is outside the thermoneutral zone [Lee et al. (4) have themselves reported a statistically significant metabolic increase by (at least) 6% in “mild” cold exposure]. Of course, should human obesity insulate, it would not affect the principal possibility to activate brown adipose tissue by cold; the ambient temperature at which that would occur would just have to be even lower. For pharmacological activation of brown adipose tissue, which is really the intention of much work in this respect, an altered insulation would be of no consequence.
There is principally a scarcity of relevant human data on whether obesity insulates. We did indeed briefly mention (on page E211) the issue as to whether an increased insulation would be observable in water (2). However, for both mice and humans, being immersed in cold water is a rare physiological situation, and irrespective of whether adipose tissue under these circumstances would insulate or not, no relevant extrapolation to the metabolic balance in normal life could be made. To our knowledge, studies of the type used in our paper (i.e., Scholander plots) have not been performed with humans of different degrees of obesity. If the present discussions can promote such studies, it would be very beneficial.
Concerning the expected effects of obesity on surface area and thus of heat loss, we can only agree with these considerations, as they parallel those we already made in the paper, in the discussion, in our case for the ob/ob mice (see page E211) (2). Our calculations (which included the Meeh factor) indicated a 36% increase in body surface area that in a simple physical interpretation “should” lead to a similar increase in the heat loss. However, this was not seen: there was no increase in heat loss. This could mean that, coincidentally, as we stated, the extra fat in the ob/ob mouse would insulate to exactly that value. However, alternatively, this observation as such, as well as the extremely similar insulation values of around 30°C/W per mouse irrespective of degree of fatness obtained in this broad investigation, may instead induce us to question whether our textbook, i.e., physical, view of insulation is too narrow. Rather, it seems that insulation is a regulated parameter, probably actively maintained by the distribution of the circulation in the body. Why a mouse would not at any time seek to minimize heat loss in the cold is not understandable, but the large increase in heat loss (loss of dynamic insulation) seen acutely after mouse death (1) would advocate an interpretation that we should perceive insulation as a functional rather than simply physical parameter.
No conflicts of interest, financial or otherwise, are declared by the authors.
A.W.F., B.C., and J.N. drafted manuscript; A.W.F., R.I.C., G.v.E., B.C., and J.N. edited and revised manuscript; A.W.F., R.I.C., G.v.E., B.C., and J.N. approved final version of manuscript.
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