sabato, Luglio 5, 2025

A question of gene-der: why women do lose more weight than men on Keto-diet?

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Obesity and ketogenic diet

Obesity is a significant public health concern worldwide and is also closely related to cardiovascular disorders, diabetes, and cancers. In 2020, 2.6 billion people aged over five were overweight or obese, and this figure is estimated to exceed four billion by 2035. Dietary interventions for obesity have become a focal point in recent years, with various weight loss strategies being promoted. The traditional low-fat diet is widely used, but it may promote excessive carbohydrate intake, which could exacerbate weight concerns and lipid abnormalities. In contrast, ketogenic diet (KED) is an ultra-low-carbohydrate, moderate-protein, and high-fat dietary approach inducing ketosis, in which the body uses ketone bodies as its primary energy source instead of glucose. As such, KED has gained popularity as an effective weight loss strategy.

Despite the significant weight loss associated with KED, notable sex differences persist. The present study reviewed the literature on the mechanisms of KED in obesity treatment and the sex differences resulting from interactions between hormones and innate factors. In a recent study published in the journal Frontiers in Nutrition, researchers reviewed sex differences in the efficacy of KED for weight loss, revealing that men show significantly greater weight loss than women under identical KED protocols. For example, in a 45-day clinical trial, men lost an average of 11.63% of body weight compared to 8.95% in women. Females naturally have more slow-twitch muscle fibers built for endurance activities, which may make traditional exercise more effective for their weight loss than strict ketosis.

Mechanisms underlying KED

Only minimal ketones are produced under standard dietary conditions. However, KED tricks the body into mimicking a fasting state, and carbohydrate scarcity leads to the accumulation of acetyl-CoA. This triggers the liver into an overdrive, producing excess ketones, such as acetoacetate, acetone and β-hydroxybutyrate, byproducts of fat metabolism. Further, the blood-brain barrier (BBB) restricts the brain’s energy sources to ketones and glucose. During fasting, ketones account for 25% to 75% of the brain’s energy demands. Thus, KED can maintain regular brain energy supply and peripheral blood glucose levels, promote fat breakdown, and reduce lipogenesis. KD promotes weight loss through various mechanisms.

KED suppresses appetite by elevating peptide neurotransmitters (e.g. glucagon-like peptide-1) and decreasing appetite-regulating hormones (e.g. ghrelin and cholecystokinin), reducing food intake. Furthermore, KED promotes the breakdown of visceral fat, depleting liver glycogen storage and reducing visceral fat accumulation. KED also alters the gut microbiota function, which exhibits sex-specific variations such as a higher abundance of fat-metabolizing bacteria like Bacteroidetes in males, reducing short-chain fatty acid production, which impacts the gut-brain axis signaling. Gut genes react differently. When researchers altered intestinal genes in mice, females produced significantly more fat-burning enzymes (HMGCS2) suggesting women’s digestive systems might respond uniquely to diet changes.

The overview of the KED’s mechanism. Under normal metabolic conditions, glucose serves as the primary energy substrate and is metabolized into pyruvate. This pyruvate is then converted to acetyl CoA, generating oxaloacetate, which enters the TCA cycle inside mitochondria to produce ATP. However, under ketogenic dietary states, the synthesis of oxaloacetate is restricted, impeding the normal progression of the TCA cycle. Consequently, a substantial consumption of fat occurs, with processes such as fatty acid activation and β-oxidation generating acetyl-CoA, which promotes the production of ketone bodies. Subsequently, this ketogenesis process yields energy and inhibits appetite, while also shifting the brain to a “fat-fueled” energy mode.

Sex disparities in KED-related weight loss

While studies have not systematically examined the genetic underpinnings of KD-induced sex disparities, literature suggests that these differences may be intricately linked to neurotransmitter levels, genetic factors, intermediate phenotypes, and individual sensitivity to environmental stimuli. Specifically, KED reduces the levels of neurotransmitters, including serotonin, dopamine, and norepinephrine (catecholamines) which affect feeding behaviors. Catecholamines also inhibit appetite and decrease food intake, helping control calorie intake. Males accumulate fat centrally (visceral fat), which is more readily metabolized under KED conditions, while females store fat subcutaneously.

This sex-specific disparity in fat distribution could be linked to the effects of norepinephrine on regional adipose tissue, which is influenced by differing densities and affinities of adrenergic receptors, accounting for variations in KED’s weight loss effects between females and males. Further, the differential response to KED between sexes may be attributed to estrogen, which can increase the sensitivity of α-adrenergic receptors that inhibit fat breakdown.A study showed that male murine models on KED achieved weight loss and glycemic control, whereas their female counterparts had a slight weight gain, delayed onset of insulin resistance, and compromised glucose tolerance.

However, eliminating endogenous estrogen production improved glycemic control and decreased adiposity, comparable to males. Furthermore, testosterone plays a crucial role in the metabolism of proteins, fats, and carbohydrates. Evidence suggests that testosterone enhances norepinephrine-induced lipolysis in isolated adipocytes from male rats by increasing the number of β-adrenergic receptors that promote fat breakdown. Visceral fat converts testosterone into estrogen in males. A recent clinical study reported that overweight males benefit from KED through increased testicular hormone profiles, elevated testosterone/SHBG levels, and reduced obesity markers.

For premenopausal women, the menstrual cycle introduces another layer of complexity. The review highlights that during the luteal phase, elevated progesterone levels can impair insulin sensitivity and increase carbohydrate cravings, making it more difficult to achieve and maintain the state of ketosis necessary for the diet to be effective. Furthermore, sex disparities exist in immediate energy sources in resting and postprandial states. Females tend to incorporate postprandial free fatty acids (FFAs) into triglycerides, storing fat and using carbohydrates as an energy source. In contrast, males generate energy through FFA oxidation, storing carbohydrates as glycogen. As such, females following KED tend to store fat and face difficulties in fat consumption and mobilization.

KED is also reported to be effective for muscle growth. A randomized controlled trial found that individuals following KED for six weeks gained more muscle than those on a regular diet. Notably, another study found that KED may adversely affect muscle fatigue in young, healthy females, potentially influencing their perception of fatigue. This suggests that the adverse effects of KED on muscle endurance in females may influence the efficacy of weight loss. Finally, differences in brain regulation, such as the reduced potency of the energy-regulating neuropeptide pre-opiomelanocortin (POMC) in female mice, also suggest a neurobiological basis for the differing outcomes.

Concluding remarks

Taken together, obesity manifests differently in females and males, and sex differences influence the effectiveness of KED in obesity treatment. Inflammation plays a hidden role. Studies found women’s bodies naturally produce more inflammation-linked fat molecules during rest, potentially making fat breakdown harder when shifting to ketosis. Current evidence suggests that KED is most effective in males, followed by postmenopausal females, with its efficacy limited in premenopausal females. These differences could be attributed to genetics, sex hormones, the menstrual cycle, neurotransmitters, neural regulation in energy-expending brain regions, gut microbiota, and immunity.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialista in Clinical Biochemistry.

Scientific references

Jiao Y, Chen X et al. Front Nutr. 2025 Jun; 12:1600927. 

Turetta C et al. Gynecol Obstet Invest. 2025 Feb 20:1-19.

Muscogiuri G, Verde L et al. J Transl Med. 2024; 22(1):949.

Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998; specialista in Biochimica Clinica dal 2002; dottorato in Neurobiologia nel 2006; Ex-ricercatore, ha trascorso 5 anni negli USA (2004-2008) alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la Clinica Basile di catania (dal 2013) Guardia medica presso la casa di Cura Sant'Agata a Catania (del 2020) Medico penitenziario presso CC.SR. Cavadonna dal 2024. Si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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