Beyond Ketosis: Rethinking High-Fat Diets, Lipotoxicity, and Metabolic Inflexibility in Midlife Women

In recent years, the narrative that fat is metabolically neutral or even superior to carbohydrate has gained widespread traction, especially within ketogenic and carnivore circles. The popularity of these diets reflects a growing pushback against outdated low-fat dogma, and rightly so: fat is essential, satiety-promoting, and hormonally supportive when consumed appropriately.

However, as with all therapeutic strategies, context matters. Increasing clinical and mechanistic evidence suggests that high-fat diets are not universally beneficial - particularly in midlife women, where hormonal and mitochondrial shifts increase vulnerability to a lesser-discussed phenomenon: lipotoxicity.

What Is Lipotoxicity?

Lipotoxicity refers to the pathological accumulation of fatty acids and their intermediates - such as ceramides, diacylglycerols (DAGs), and acylcarnitines in non-adipose tissues like the liver, pancreas, skeletal muscle, and heart (Unger & Scherer, 2010). These tissues are not designed to store large amounts of fat. When fatty acid delivery exceeds mitochondrial oxidation capacity, these lipids accumulate and begin to interfere with cellular function. The result? Impaired insulin signalling, oxidative stress, mitochondrial dysfunction, and local inflammation - all of which drive metabolic dysregulation and disease progression (Samuel & Shulman, 2016).

The Role of Mitochondrial Overload

This process is most concerning when fatty acid intake exceeds the ability of the mitochondria to oxidise them for energy - a threshold that varies depending on metabolic health, hormonal status, and physical activity. In insulin-resistant states, mitochondrial flexibility is impaired, meaning fatty acids are not efficiently burned. Instead, they spill over into circulation and infiltrate tissues, triggering cellular stress and inflammatory cascades (Listenberger et al., 2003). This phenomenon may explain why some individuals experience paradoxical weight gain, rising insulin levels, or increased fatigue on low-carb, high-fat (LCHF) protocols despite adherence to a “clean” diet.

Midlife Women: A Unique Metabolic Terrain

Lipotoxicity risk is particularly relevant for perimenopausal and menopausal women, where metabolic flexibility is naturally reduced. As oestrogen declines, there is a shift in fat distribution, a downregulation of adiponectin, and impaired lipid partitioning - collectively lowering the capacity to safely store or oxidise fat (Carr, 2003; Mauvais-Jarvis, 2015). At the same time, mitochondrial density and efficiency decline, making the system more vulnerable to energy overload.

In this context, high-fat diets - particularly those high in saturated fat, may backfire. Women may experience increasing fasting insulin, elevated triglycerides, reduced HDL, and worsening HOMA-IR, even when eating few carbohydrates. Adiponectin levels, which promote insulin sensitivity and fatty acid oxidation, often decline with age and visceral adiposity, compounding the issue (Matsuzawa et al., 2004).

Silent Hepatic Insulin Resistance

Lipotoxicity also drives hepatic insulin resistance. Excess free fatty acids entering the liver are re-esterified into triglycerides or shunted into pathways that interfere with insulin signalling. This hepatic resistance is often “silent” on standard blood tests, manifesting as compensatory hyperinsulinaemia - the body’s attempt to suppress further lipolysis and manage glucose levels. Over time, this elevates fat storage, impairs satiety signalling, and promotes inflammatory tone (Petersen & Shulman, 2018).

The Myth of Leanness as Metabolic Health

This also disrupts the popular assumption that lean body composition equates to metabolic wellness. Many women with normal or low BMI still display poor glycaemic control, central adiposity, low adiponectin, or high postprandial triglycerides. Conversely, some with higher BMIs maintain strong insulin sensitivity and mitochondrial robustness - highlighting that adaptive capacity, not size, is the true measure of metabolic health.

Clinical Patterns: When High-Fat Stops Working

In clinical practice, signs of fat overload often present subtly. Clients may report:

• Rising fasting glucose or insulin despite strict carb restriction

• Increased fatigue or sluggishness after meals

• Digestive symptoms tied to poor bile flow (especially with gallbladder insufficiency)

• Plateaus or paradoxical weight gain on ketogenic or carnivore protocols

• Worsening sleep, skin health, or inflammatory markers despite adherence

These patterns point to a mismatch between dietary fat intake and the body’s ability to process it - a signal that the mitochondria, bile system, or hormonal axis may be overburdened.

A More Nuanced Strategy

In these cases, the solution is not simply “more fat” or “fewer carbs,” but restoring metabolic flexibility through targeted interventions:

• Reduce total dietary fat, especially saturated fat, and prioritise mono- and polyunsaturated fats for improved lipid handling

• Support bile flow and fat emulsification via bitters, taurine, choline, or ox bile where indicated

• Enhance mitochondrial function through nutrients like carnitine, CoQ10, alpha-lipoic acid, and magnesium

• Time carbohydrates strategically, particularly around exercise or earlier in the day to support cortisol rhythms and thyroid function

• Restore circadian alignment - as disrupted light exposure impairs insulin sensitivity and metabolic signalling (Chellappa et al., 2019)

Conclusion

High-fat, low-carb diets have a therapeutic role, but only when the metabolic system is primed to handle them. In midlife women with declining hormonal resilience and mitochondrial capacity, excessive fat intake may tip the system into lipotoxic overload. Metabolic health isn’t defined by macronutrient ideology, it’s defined by adaptability, tissue resilience, and mitochondrial capacity.

The future of personalised nutrition lies not in dietary camps, but in identifying when a strategy stops serving the body and knowing how to pivot with clinical intelligence.

References:

• Unger RH, Scherer PE. (2010). Gluttony, sloth and the metabolic syndrome: a roadmap to lipotoxicity. Trends in Endocrinology & Metabolism, 21(6), 345–352.

• Samuel VT, Shulman GI. (2016). The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest, 126(1), 12–22.

• Listenberger LL et al. (2003). Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proceedings of the National Academy of Sciences, 100(6), 3077–3082.

• Carr MC. (2003). The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab, 88(6), 2404–2411.

• Mauvais-Jarvis F. (2015). Sex differences in metabolic homeostasis, diabetes, and obesity. Biol Sex Differ, 6(1), 14.

• Matsuzawa Y et al. (2004). Adiponectin and metabolic syndrome. Arteriosclerosis, Thrombosis, and Vascular Biology, 24(1), 29–33.

• Petersen KF, Shulman GI. (2018). Mechanisms of insulin action and insulin resistance. Physiol Rev, 98(4), 2133–2223.

• Chellappa SL et al. (2019). Circadian disruption and human health: A bidirectional relationship. Trends in Endocrinology & Metabolism, 30(7), 460–473.