These various fat deposits are also regulated over time by the changing flux of sex hormones, so LPL can be considered the point at which insulin and sex hormones interact to determine how and when we fatten. The male sex hormone testosterone, for instance, suppresses LPL activity in the abdominal fat, but has little or no effect on the LPL in the fat of the hips and buttocks. Increasing fat accumulation in the abdomen as men age may therefore be a product of both increasing insulin and decreasing testosterone. The female sex hormone progesterone increases the activity of LPL, particularly in the hips and buttocks, but estrogen, another female sex hormone, decreases LPL activity.*120 It’s the decrease in estrogen secretion during menopause—and so the increase in LPL activity—that may explain why women frequently gain weight as they pass through menopause. The effect of decreasing estrogen secretion on LPL activity would also explain why women typically fatten after the removal of the uterus in a hysterectomy. The change in hormonal regulation of LPL also explains how and why fat deposition changes during pregnancy and, after birth, with nursing.

In 1981, M. R. C. Greenwood, who was a student of Jules Hirsch and was then at Vassar College, proposed what she called the “gatekeeper hypothesis” of obesity, based on the hormonal regulation of LPL. “Conditions which favor increases in adipose tissue LPL,” Greenwood wrote, “result in increased fat accumulation and, when food intake is constant, lead to alterations in body composition.” Greenwood proposed the hypothesis based on her studies of the obese strain of rats known as Zucker rats, in which LPL activity in the fat tissue is elevated in the womb—apparently the effect of fetal hyperinsulinemia, though it then persists well into adulthood. As a result, Zucker rats grow monstrously obese. But they will actually lay down more fat, Greenwood reported, if they’re kept to a strict diet than they will if they’re allowed to eat freely to satisfy their hunger. The less they’re allowed to eat, however, the smaller their muscles will be; their brains and kidneys will also be “significantly reduced” in size. “In order to develop this obese body composition in the face of calorie restriction,” Greenwood wrote, “several developing organ systems in the obese rats were compromised.”