Beyond Activation: Why Building Brown Fat May Succeed Where Waking It Up Failed

Beyond Activation: Why Building Brown Fat May Succeed Where Waking It Up Failed

In the late 1980s and throughout the 1990s, several large pharmaceutical companies tried to develop obesity drugs that would acutely activate thermogenesis  - the body’s process of dissipating energy as heat. The idea was to increase resting metabolic rate and turn stored fat into heat by stimulating the activity of brown fat (thermogenic fat).

This effort grew out of the discovery of the β3-adrenergic receptor (β3-AR) [1, 2]. In rodents, compounds that activated this receptor increased thermogenesis in brown fat and caused substantial weight loss, largely by reducing body fat and without reducing food intake. These findings led companies to develop drugs designed to selectively activate the human version of β3-AR, with the hope of reproducing those results in patients.

But these programs were much less successful in humans than in rodents, for both safety and efficacy reasons.

On the safety side, compounds aimed at the human β3-AR were not fully selective. At doses high enough to work, they also activated related receptors, β1-AR and β2-AR, which caused side effects including increased heart rate, higher blood pressure, and tremor [3, 4, 5].

On the efficacy side, the effects seen in rodents did not translate well to humans. This is partly because human brown fat cells contain much less β3-AR than rodent brown fat cells, and also because human brown fat relies less on β3-AR signaling overall [4, 5, 6, 7, 8].

There is also an important biological difference between rodents and humans. Rodents housed at normal laboratory temperatures are actually cold relative to their preferred temperature, so they maintain a large amount of brown fat to generate heat. Humans at room temperature do not have the same need, so they maintain much less brown fat. Moreover, obese humans have even less brown fat than lean individuals [3, 9, 10, 11, 12, 13]. As a result, simply stimulating the existing brown fat in humans did not produce the large energy expenditure seen in rodents.

These findings led to two key conclusions:

1. β3-AR is not a suitable obesity target in humans.
2. To achieve meaningful anti-obesity effects in humans, it is necessary to increase brown fat mass – that is, the number of thermogenic fat cells – rather than merely activate the limited number already present.

That insight was important, but it was not enough on its own. Researchers still needed a way to reliably increase human brown fat.

A major step forward came with the discovery of the first human brown fat adult stem, or progenitor, cells [14]. Energesis’ founders used these cells to build a screening platform for finding drug targets and compounds that can drive these progenitor cells to become new, active brown fat cells [3]. These new thermogenic fat cells consume large amounts of glucose and fatty acids, and in animal models of obesity produce highly significant weight loss, all of which is from fat.

Energesis has therefore taken a different approach from earlier brown fat programs. Instead of trying to wake up the limited brown fat already present, the goal is to create more of it by targeting brown fat stem/progenitor cells. Our research focus now is to advance the most promising drug candidates into testing in higher species, including humans, with the aim of developing safe new treatments for obesity that increase energy expenditure through brown fat.

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