One of the most significant energy demands that a female animal will face at any time in her life is when she is feeding her young. Unlike the intense bursts of energy that we routinely expend in daily life, lactation is a sustained demand that lasts over an extensive period of time. An important question is what limits an animal’s capacity to output energy, for example in the form of milk production? Is this capacity intrinsically limited by the amount of energy that the animal can absorb across the gut lining (e.g. centrally limited), or, is it limited by the organ that is responsible for the energy output, in this case the mammary gland (peripherally limited). This debate raged for several years, and some had thought that it had been laid to rest primarily by the work of Kimberly Hammond and Jared Diamond. In the early 1990s, they described experiments that indicated that the limit appeared to be conferred by the mammary gland in Swiss Webster mice. Hammond had found that she couldn’t get the mice to ingest more food, ‘they’d (even) kill their young before they ate more’ explains John Speakman. However, when she tested how the mice responded to the cold, she noticed that they increased their food intake. This seemed to lay the question to rest: energy intake was not limited centrally by the gut, because the mice had eaten more in cold conditions, so the mammary gland must be the culprit. Sustained energy intake must be peripherally limited, by the mammary gland.

Five years ago, Speakman and colleagues published a similar study on a different strain of Mus musculus, MF1, which made him suspect that these little critters weren’t behaving like their Swiss Webster cousins and made him think that the issue wasn’t cut and dried. So, Speakman put them to the test to see just how far they could, or would, go.

In the first of five, back-to-back publications in this issue, Speakman and his team tried to get the mice to eat more by modifying the litter size (p. 1925). The result was that even if they increased the litter size to 18, the mothers didn’t increase their food intake beyond 23 g day–1. But, when the litter size was decreased, they responded by reducing the amount they consumed.

In a series of follow-up experiments, they stressed the mice to see if there were any circumstances that would force them to exceed the 23 g day–1 asymptote. An effective way of increasing the energy demand on lactating animals is to cause a second pregnancy while the mice are still feeding the first litter (p. 1947). Even these extra demands didn’t push their daily diet above 23 g day–1. However these mice did exceed the 23 g limit during the second lactation. This suggested that the mice weren’t limited by the amount of food that they can transport across the gut, supporting Hammond’s original interpretation that the mammary gland is the dominant limiting factor.

In the next test, the mice were fed a reduced energy diet (p. 1957). Surprisingly, these mice also exceeded the 23 g day–1 asymptote. So it wasn’t that they couldn’t eat more, they can increase their intake when they choose, apparently confirming that the mammary gland is the limiting factor.

In the final test, they tried stressing the mice under cold conditions to see how that affected their energy intake, and this time they found that not only did the mice eat more, but they produced more milk (p. 1967). In this case, the mammary gland was not limiting milk production. Hammond’s earlier experiments had found that cold was the only condition where the Swiss Webster mice ate more, but she hadn’t explicitly looked at milk production. When Speakman’s group measured the milk output, they found the increase. So, if the mammary gland is not the limiting factor, what is?

Speakman decided to test whether resting metabolic rate was somehow related to the limiting factor (p. 1937). He tested to see if variation in resting metabolic rate was correlated with the amount that the mice could eat, and therefore the possible amount of energy that they have available for lactation. If resting metabolic rate was the factor that potentiated milk production, then animals with a lower resting metabolic rate may be more limited in lactation than others with a higher rate. But, the only correlation that he found was that bigger mums, which have higher resting metabolic rates, had larger litters of bigger pups. Once the effect of body weight had been taken into account, the animal’s resting metabolic rate didn’t appear to be a significant factor, leaving the question wide open.

In most circumstances, the mice appeared to be limited in the amount of energy that they could intake or output. But were they really, or was this more of a choice than a hard wired response? Most of the observations were taken during the first pregnancy. How would the mice respond during later lactations? After all, the mice had worked harder and increased their intake during their second lactation. This raises the possibility that the female mice were trading off a lower yield in their first pregnancy to maximise their life-time pup production. Were they able to do this because they had ‘saved themselves’ by not over extending themselves during the first lactation? Whether it’s a physical limit or a matter of choice, the jury is out on the question of energy balance. What guides these choices is the new question, and that will form the focus of much work in this and other systems.

Biological systems are finely tuned and optimised to function within tightly constrained temperature ranges. But take an organism out of its comfort zone and its delicate biological balance can be disturbed to the extent that life itself is threatened. The Heat-shock proteins (Hsp) are in the cell’s front line of molecular defences against environmental stress. They are chaperones that protect the cell by preventing heat-damaged proteins from aggregating during a high temperature episode. Of the many chaperone proteins expressed during a heat shock response, Hsp70 is the most abundant.

Work from Martin Feder’s lab in the mid 1990s showed that Drosophila melanogaster which had been genetically engineered to carry extra hsp70 genes were more resistant to high temperatures than regular lab flies. These ‘extra copy’ flies produced more Hsp70, and survived temperatures up to 36°C that would kill weaker fly strains. The climate in sub-Saharan Africa routinely reaches such highs, and a strain of Drosophila that was collected in Chad in the early 1970s, has evolved to withstand the fiery climate. Feder knew he could improve thermal tolerance by boosting hsp70 gene levels, but by what means had nature achieved this naturally in the African flies?

Using a battery of molecular techniques Feder and his Russian co-workers compared the African flies with Drosophila from a temperate climate to see how the flies deploy heat-shock chaperones to combat the potentially lethal temperatures. They followed the transcription of hsp70 genes and Hsp70 protein levels at temperatures from 36–41°C. What they found was perplexing. Not only did the African flies have little inducible thermotolerance, but Hsp70 levels were also much lower than in typical Drosophila!

Why would a population evolve decreased expression of heat-shock proteins? Like human fire fighters, heat-shock proteins are extremely important in preventing heat damage, but can do damage in their own right when ‘putting out the fire’. These side-effects include interference with growth and development. The authors speculate that evolution has opted to reduce heat-shock expression (and inducible thermotolerance) in the African flies rather than chronically expose them to low level side-effects. So how has Mother Nature turned down heat-shock protein expression in the African flies? The heat-shock transcription factor (HSF), which regulates transcription of the heat-shock genes by binding to their promoters, itself appears normal in its behaviour although transcription is reduced. A possible explanation is that mobile genetic elements have disrupted the heat-shock promoter, reducing interaction between bound HSF and the transcriptional apparatus. Indeed, the authors report that two different mobile elements have inserted themselves into two different heat-shock gene clusters of the African flies. Although the impact of these mobile elements on heat-shock transcription awaits verification, Nature may have exploited the elements to make the flies from Chad not so hot in their heat-shock response.