Research: Fasting, and the Science Behind It
"Humans have been hunter-gatherers for two million years; it was only a relatively short 12,000 years ago that the transition to agriculture occured. Thus, post-agricultural humans may not have had sufficient time to fully adapt to the continuous food supply provided by farming, which may in part explain the later introduction of voluntary fasting practices by the majority of civilizations on earth. The ancient Romans, for example, believed that eating more than one large meal per day was unhealthy. Most world religions, including Christianity and Islam, also incorporated regular fasting into their religious practices." - Phillips, MCL, Exposure to Exogenous Estrogen Through Intake of Commercail Milk Produced from Pregnant Cows.
Intermittent fasting two days versus one day per week, matched for total energy intake and expenditure, increases weight loss in overweight/obese men and women
Arciero, P.J., Arciero, K.M., Poe, M. et al. Intermittent fasting two days versus one day per week, matched for total energy intake and expenditure, increases weight loss in overweight/obese men and women. Nutr J 21, 36 (2022). https://doi.org/10.1186/s12937-022-00790-0
Full paper at:
https://rdcu.be/douCe
ABSTRACT:
Fasting is deeply entrenched in evolution, yet its potential applications to today’s most common, disabling neurological diseases remain relatively unexplored. Fasting induces an altered metabolic state that optimizes neuron bioenergetics, plasticity, and resilience in a way that may counteract a broad array of neurological disorders. In both animals and humans, fasting prevents and treats the metabolic syndrome, a major risk factor for many neurological diseases. In animals, fasting probably prevents the formation of tumors, possibly treats established tumors, and improves tumor responses to chemotherapy. In human cancers, including cancers that involve the brain, fasting ameliorates chemotherapy-related adverse effects and may protect normal cells from chemotherapy. Fasting improves cognition, stalls age-related cognitive decline, usually slows neurodegeneration, reduces brain damage and enhances functional recovery after stroke, and mitigates the pathological and clinical features of epilepsy and multiple sclerosis in animal models. Primarily due to a lack of research, the evidence supporting fasting as a treatment in human neurological disorders, including neurodegeneration, stroke, epilepsy, and multiple sclerosis, is indirect or non-existent. Given the strength of the animal evidence, many exciting discoveries may lie ahead, awaiting future investigations into the viability of fasting as a therapy in neurological disease.
Intermittent fasting two days versus one day per week, matched for total energy intake and expenditure, increases weight loss in overweight/obese men and women
Arciero, P.J., Arciero, K.M., Poe, M. et al. Intermittent fasting two days versus one day per week, matched for total energy intake and expenditure, increases weight loss in overweight/obese men and women. Nutr J 21, 36 (2022). https://doi.org/10.1186/s12937-022-00790-0
Full paper at:
https://rdcu.be/douCe
ABSTRACT:
Fasting is deeply entrenched in evolution, yet its potential applications to today’s most common, disabling neurological diseases remain relatively unexplored. Fasting induces an altered metabolic state that optimizes neuron bioenergetics, plasticity, and resilience in a way that may counteract a broad array of neurological disorders. In both animals and humans, fasting prevents and treats the metabolic syndrome, a major risk factor for many neurological diseases. In animals, fasting probably prevents the formation of tumors, possibly treats established tumors, and improves tumor responses to chemotherapy. In human cancers, including cancers that involve the brain, fasting ameliorates chemotherapy-related adverse effects and may protect normal cells from chemotherapy. Fasting improves cognition, stalls age-related cognitive decline, usually slows neurodegeneration, reduces brain damage and enhances functional recovery after stroke, and mitigates the pathological and clinical features of epilepsy and multiple sclerosis in animal models. Primarily due to a lack of research, the evidence supporting fasting as a treatment in human neurological disorders, including neurodegeneration, stroke, epilepsy, and multiple sclerosis, is indirect or non-existent. Given the strength of the animal evidence, many exciting discoveries may lie ahead, awaiting future investigations into the viability of fasting as a therapy in neurological disease.
Leptin
Ahima RS, Flier JS. Leptin. Annu Rev Physiol. 2000;62:413-37. doi: 10.1146/annurev.physiol.62.1.413. PMID: 10845097.
ABSTRACT:
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 (156–158). 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 (48, 151)."
"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 (67, 151, 160)."
"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 (48, 162–164). Similarly, pertubations of the reproductive axis as a result of starvation develop more rapidly in rodents than humans (48, 165)."
"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 (65, 116). 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 (112, 170)."
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 (13, 180, 181). 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)."
"...in addition to increasing energy expenditure (at least in rodents) (13, 184), 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."
Ahima RS, Flier JS. Leptin. Annu Rev Physiol. 2000;62:413-37. doi: 10.1146/annurev.physiol.62.1.413. PMID: 10845097.
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