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Research:  Fasting, and the Science Behind It

Current research suggests that the body has a defended fat mass set point, which is regulated through the hormone leptin and various physiological adaptations.


The concept of a defended fat mass set point refers to the idea that the body has a natural mechanism to regulate and maintain a specific level of body fat. Research on this topic suggests that the body defends against both weight loss and weight gain, aiming to keep individuals within a certain range of body fat.

Several studies have explored the mechanisms behind the defended fat mass set point. One key factor is the hormone leptin, which is produced by fat cells and plays a crucial role in regulating energy balance and body weight. Leptin acts on the hypothalamus in the brain, influencing appetite, metabolism, and energy expenditure.

When an individual loses weight, the fat cells release less leptin, signaling a state of energy deficit to the brain. In response, various physiological adaptations occur, such as increased hunger, reduced metabolic rate, and enhanced efficiency in utilizing energy. These changes work together to restore lost weight and defend against further weight loss, ultimately bringing the body back to its predetermined fat mass set point.

On the other hand, weight gain also triggers adjustments in the body. As fat mass increases, leptin levels rise, sending signals to the brain to suppress appetite and increase energy expenditure. This mechanism helps prevent excessive weight gain and maintain the defended fat mass set point.

Although the defended fat mass set point is an important concept in understanding weight regulation, it is not yet fully understood. There are individual differences in set points, and they can be influenced by various factors such as genetics, environment, and lifestyle. Furthermore, external factors like dieting and chronic overeating can potentially shift the set point over time.

In practice, we see significant indications in our clients that they experience set points as they lose weight. We employ a number of methodologies to break through these perceived set points, allowing the client to continue to lose weight and establish a new, lower set point.


Note that a true set point, and a mere weight loss plateau, can be hard to distinguish without significant experience and understanding of a person's history, diet, exercise, and health. That said, we're almost always able to make that distinction - its one of the major reasons coaching can be so useful for weight loss clients.


Further studies are needed to fully elucidate the mechanisms involved in defended fat mass set point. FUEL will continue to explore successful interventions for both true set point, and for lesser plateaus caused by other issues.

Central nervous system control of food intake

Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000 Apr 6;404(6778):661-71. doi: 10.1038/35007534. PMID: 10766253.


New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.

Some Key Points:

Paper's Focus


This paper discusses the central nervous system's involvement in regulating food intake, including the role of hypothalamic circuits and the interaction with hormones like leptin.


Ahima RS, Flier JS. Leptin. Annu Rev Physiol. 2000;62:413-37. doi: 10.1146/annurev.physiol.62.1.413. PMID: 10845097.

Full paper at:


The discovery of the adipose-derived hormone leptin has generated enormous interest in the interaction between peripheral signals and brain targets involved in the regulation of feeding and energy balance. Plasma leptin levels correlate with fat stores and respond to changes in energy balance. It was initially proposed that leptin serves a primary role as an anti-obesity hormone, but this role is commonly thwarted by leptin resistance. Leptin also serves as a mediator of the adaptation to fasting, and this role may be the primary function for which the molecule evolved. There is increasing evidence that leptin has systemic effects apart from those related to energy homeostasis, including regulation of neuroendocrine and immune function and a role in development.

Some Key Points:

General Points on Leptin

"[B]ecause leptin levels do not rise in response to individual meals (37), leptin is not likely to serve as a meal-related satiety signal."

"Regulation of leptin expression by nutrition is probably mediated in part by insulin."

"Initial studies indicated that leptin expression was synthesized only in adipose tissue. However, leptin is also synthesized in extra-adipose tissues including placenta, gastric fundic mucosa, skeletal muscle, and mammary epithelium."

Leptin As Anti-Obesity Hormone

"Hyperleptinemia is thought to be indicative of leptin resistance, which may play a role in the development of obesity."

"Mechanisms thought to underlie leptin resistance include dysregulation of leptin synthesis and/or secretion, abnormalities of brain leptin transport, and abnormalities of leptin receptors and/or post-receptor signaling."

"However, there is as yet no direct explanation of the apparent lack of sensitivity of individuals to elevated leptin levels during the course of diet-induced obesity."

"...leptin resistance may arise from defects of receptor-mediated leptin transport into the brain (95). A polygenic mutation that leads to late onset obesity in New Zealand obese (NZO) mice may also offer some insight into the role of brain leptin transport in obesity. These mice are resistant to peripheral leptin administration, but do respond to intracerebroventricular leptin injection, consistent with defective brain leptin transport (148). Similarly, diet-induced obesity in rodents is characterized by insensitivity to peripheral leptin injection (154) but respond to intracerebroventricular leptin (154). In contrast, agouti (Ay/a ) mice have impaired melanocortin (MC4) receptor signaling in the brain and are resistant to both peripheral and central leptin injection (148). Studies of leptin transport into brain in these models have not been reported."

"The role of leptin in body weight regulation may involve interactions with other metabolic signals, notably insulin and glucocorticoids (67). These hormones regulate the expression of similar neuropeptides in brain regions involved in feeding behavior and body weight regulation. Glucocorticoids have a permissive effect on obesity, as evidenced by the ability of adrenalectomy to ameliorate obesity (156158). Conversely, hypercortisolism leads to abnormalities of adipose distribution (159). Further studies are needed to understand the interactions among these metabolic hormones."

Leptin As a Signal for Adaptation to Fasting

"The widespread occurrence of leptin-resistant obesity may reflect the fact that inability to store energy efficiently at times of abundance is evolutionarily disadvantageous (151). According to this view, the dominant role of leptin in energy homeostasis is likely to be as a mediator of the adaptation to fasting (48151)."

"Starvation triggers complex neural, metabolic, hormonal, and behavioral adaptations with the goal of maintaining the supply of energy substrates for use by the brain, protecting lean mass, and promoting survival. A major aspect of this adaptation is the capacity to switch from carbodydrate- to fat-based metabolism during fasting. This change is mediated predominantly by a fall in insulin and rise in counteregulatory hormones, i.e. glucagon, epinephrine, and glucocorticoids (67151160)."


"Other adaptations to starvation include a decrease in thyroid and gonadal hormones, increased adrenal glucocorticoids, decreased body temperature, and increased appetite. The net effect of these adaptations is to stimulate gluconeogenesis to provide glucose for vital cellular function and supply fatty acids for use by skeletal muscle. Energy utilization is minimized during fasting, in part through suppression of thyroid thermogenesis and curtailment of procreation and growth. In addition, starvation is characterized by immune suppression, including decreased lymphocyte proliferation and helper T-cell cytokine production (161). The changes in thyroid hormones, glucocorticoids, and in body temperature are prominent in rodents but limited in humans (48162164). Similarly, pertubations of the reproductive axis as a result of starvation develop more rapidly in rodents than humans (48165)."


"Low leptin levels may contribute to the development of obesity. Leptin is inappropriately low (as a function of body fat) in some obese individuals (168); however, it is not known whether these individuals have defective leptin synthesis and/or release, and this finding has not yet been observed in all populations (169). Although the functional implications of this observation are yet to be determined, it is plausible that relatively low leptin is perceived as a starvation signal, leading to increased appetite and efficient energy utilization. In contrast, elevation of leptin levels may predispose to cachexia in patients with renal failure and infections by inhibiting appetite and increasing energy expenditure (65116). The plasma:CSF leptin ratio is normal in patients with anorexia nervosa during refeeding (prior to weight restoration) and may create a premature sense of satiety during refeeding (112170)."

Other Effects of Leptin

"Leptin exerts acute effects on metabolism, independent of its role in long-term body weight regulation."


"Leptin stimulates lipolysis, alters lipid partitioning in skeletal muscle, and is capable of increasing fatty acid synthesis in the liver (13180181). The extent to which these effects are mediated directly on peripheral targets or through the central nervous system is as yet unsettled."


"Local leptin expression in the stomach has been postulated to regulate satiety (75)."


" addition to increasing energy expenditure (at least in rodents) (13184), leptin may be involved in the regulation of cardiovascular and renal function via the central nervous system (183). Such a role may have important implications for the development of cardiovascular and renal complications in obesity and related diseases."

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