The Gravitostat Regulates Fat Mass in Obese Male Mice While Leptin Regulates Fat Mass in Lean Male Mice

Abstract

Leptin has been the only known homeostatic regulator of fat mass, but we recently found evidence for a second one, named the gravitostat. In the current study, we compared the effects of leptin and increased loading (gravitostat stimulation) on fat mass in mice with different levels of body weight (lean, overweight, and obese). Leptin infusion suppressed body weight and fat mass in lean mice given normal chow but not in overweight or obese mice given a high-fat diet for 4 and 8 weeks, respectively. The maximum effect of leptin on body weight and fat mass was obtained already at <44 ng/mL of serum leptin. Increased loading using intraperitoneal capsules with different weights decreased body weight in overweight and obese mice. Although the implantation of an empty capsule reduced the body weight in lean mice, only a nonsignificant tendency of a specific effect of increased loading was observed in the lean mice. These findings demonstrate that the gravitostat regulates fat mass in obese mice, whereas leptin regulates fat mass only in lean mice with low endogenous serum leptin levels. We propose that activation of the gravitostat primarily protects against obesity, whereas low levels of leptin protect against undernutrition.

The gravitostat theory: More data needed

“…We thank Drs Thivel and Boirie for bringing up additional aspects of our recent randomized clinical trial published in EClinicalMedicine [1] on the hypothetical body weight regulating system that we previously coined “the gravitostat” [2] . As pointed out by Thivel and Boirie, [3] in several preclinical studies, we found that activation of the gravitostat by increased loading decreases fat mass substantially, while there is little or no effect on fat free mass in obese experimental animals [2 , 4 , 5] . In our recent proof-of-concept randomized clinical trial we found that increased weight loading for 3 weeks reduces body weight and body fat mass, but not fat free mass, also in obese humans [1] .…”

Displacing Sedentary Behaviour with Light Intensity Physical Activity Spontaneously Alters Habitual Macronutrient Intake and Enhances Dietary Quality in Older Females

“…We failed to observe any significant change in energy intake. Accordingly, “the gravitostat” exclusively mediates reduced energy intake following sustained postural transition in rodents [ 34 , 35 ]. Furthermore sedentary behaviour displacement reduces subsequent energy intake in younger adults [ 36 ].…”

“…In contrast, the current study will have loaded the gravitostat only with bodyweight whenever sitting was replaced with standing/light activity over eight weeks. In rodents, the energy intake reducing effect of the “gravitostat” appears to be dependent on an osteocyte strain detection mechanism, which is activated in response to high loading through the lower limbs [ 34 , 35 ]. However, the current lack of observed change in energy intake persisted even after adjustment for baseline BMI.…”

“…Acutely displacing sedentary time in younger adults with standing marginally increases energy expenditure [ 18 , 33 ], suggesting that a reduced obesity risk with a high standing time may primarily be due to a reduced energy intake. Accordingly, sustained postural transition in rodents results in a reduced energy intake [ 34 ], which appears to be exclusively dependent on an osteocyte strain detection mechanism (termed “the gravitostat”), activated as an effector in response to increased loading through the lower limbs [ 35 ]. In support of this notion, relative energy intake during a subsequent meal was 39% lower following a LIPA breaks protocol compared to continuous sedentary behaviour in young adults [ 36 ].…”

The Gravitostat theory: Body fat is lost but is fat-free mass preserved?

“…Based on their previous fundamental experiments conducted in animals and clearly showing the effects of hypergravity on body mass and body fat, supporting then the Gravitostat hypothesis [ 1 , 2 ], Ohlsson and colleagues recently confronted their findings in humans, artificially increasing the body weight (weight loading) of 69 adults with moderate obesity [3] . Using a proof of concept translational randomized clinical trial, the authors, in line with their previous results obtained in rodents [ 1 , 2 ], observed a significant reduction of their participants’ body weight and especially fat mass loss, suggesting the existence of a weight loading dependent homeostatic regulation of body weight in human (the Gravitostat theory).…”