Why Your Body Doesn’t Feel Full in Perimenopause: A Physician’s Look at Leptin

Written and edited by Sarah Bonza MD, MPH, MSCP, FAAFP, DipABLM, NBC-HWC

Healthy eating during perimenopause

As a board-certified family physician trained in functional medicine, lifestyle medicine, and menopause therapy, I have seen how shifts in hormone balance during the perimenopausal years can affect health in unexpected ways. One frequently overlooked yet significant factor is the role of leptin.

A Personal Account of Leptin Insensitivity

As I approached my own perimenopausal transition, I noticed stubborn weight gain around my waist and persistent hunger even after meals that should have been filling. It felt as though the internal switch that signals fullness had broken.

In time, I discovered that I was contending with leptin insensitivity, a condition in which the body produces sufficient or even excessive leptin, yet the brain does not respond to it. This understanding prompted me to examine leptin’s influence on metabolism more closely.

Leptin: Communicating Fullness to the Brain

Leptin, primarily produced by adipose tissue, is responsible for sending signals to the hypothalamus about energy stores and when to reduce food intake. Under ideal circumstances, leptin helps maintain a stable body weight and balanced energy levels [1]. However, when perimenopause sets in, fluctuations in estrogen and other hormones may reduce the brain’s sensitivity to leptin [2]. Even if the bloodstream carries ample leptin, the signal may not register, leading to overeating and weight gain.

Leptin communicating fullness to the brain during perimenopause

What Happens During Perimenopause?

In perimenopause, declining and erratic estrogen levels can interfere with leptin signaling [2]. As a result, women may experience leptin resistance, where abundant leptin fails to curb appetite effectively.

The difficulty compounds as abdominal fat increases, producing even more leptin and perpetuating a cycle of resistance. It can be challenging to break away from this pattern without understanding leptin’s role.

Stress and Leptin Resistance

Additional stressors during perimenopause further complicate matters. Chronic stress raises cortisol levels, which can interfere with leptin’s ability to relay fullness signals [3]. Many women — myself included — have found themselves caught in a loop of seeking out “comfort foods” after stressful days, even though physical hunger is not the true driver.

Leptin, Metabolism, and Hormonal Interplay

Leptin resistance does not occur in isolation. As estrogen declines, the risk of insulin resistance rises [4]. Insulin resistance can worsen leptin resistance, linking these metabolic shifts in a feedback loop that affects both appetite and body composition. Increased central adiposity only heightens the disconnect between leptin production and reception.

GLP-1 Medications and Leptin

Certain medications, such as glucagon-like peptide-1 (GLP-1) receptor agonists, including semaglutide (Ozempic, Wegovy), liraglutide (Victoza), dulaglutide (Trulicity), exenatide (Byetta, Bydureon), and lixisenatide (Adlyxin).often used for weight management and glycemic control, may indirectly improve leptin signaling by reducing overeating and stabilizing body weight. There is evidence that GLP-1 and leptin pathways may interact in the brain, potentially enhancing the effectiveness of leptin’s messages over time [5].

GLP-1 and its effects on the pancreas, brain, and stomach

Evidence-Based Strategies for Supporting Leptin Sensitivity

Aerobic activity in perimenopause

1. Regular Physical Activity:
   Exercise, including aerobic activities and resistance training, can support metabolic health and improve both insulin and leptin sensitivity. Increasing muscle mass and optimizing metabolic function may help restore the body’s ability to respond to leptin [6].
2. Whole-Food Dietary Patterns:
   Emphasizing vegetables, fruits, whole grains, legumes, lean proteins, and healthy fats helps maintain stable blood sugar and supports leptin’s signals. Minimizing highly processed foods can reduce inflammation and hormonal imbalances that hinder proper leptin function.
3. Prioritizing Sleep Quality:
   Adequate, restful sleep helps maintain a healthy ratio of leptin to ghrelin (the hunger hormone). Poor sleep patterns have been linked to lower leptin, higher ghrelin, and greater appetite [7]. Ensuring 7–9 hours of quality sleep can support metabolic stability.
4. Managing Stress Levels:
   Techniques such as meditation, gentle yoga, or controlled breathing can help reduce cortisol levels and gradually improve leptin responsiveness. Addressing stress allows better recognition of true hunger rather than emotional urges.
5. Targeted Supplements:

• Berberine: Research suggests berberine may improve insulin sensitivity and reduce inflammation, potentially influencing leptin signaling indirectly [8].
• Omega-3 Fatty Acids: Consuming omega-3s can support metabolic health and may help normalize leptin responsiveness [9].

6. Attentive Eating Habits:
Eating slowly and without distractions can help individuals perceive the subtle fullness cues that leptin provides. This reestablishes trust in internal signals rather than relying on external dieting rules.

A More Informed Perspective on Perimenopause

Improving leptin sensitivity is about recognizing the complex metabolic changes that occur as estrogen fluctuates and ultimately, wanes. By integrating structured activity, nutrient-rich foods, sleep hygiene, stress reduction, and judicious supplementation, women may reclaim a more comfortable and balanced metabolic state during perimenopause.

Each woman’s experience is different. By approaching these years with patience, self-awareness, and a willingness to adapt strategies, it’s possible to achieve meaningful changes. Drawing upon both clinical expertise and personal experience, I encourage women to view this time not merely as a challenge, but as an opportunity to better understand the body’s signals and foster long-term metabolic well-being.

References

1. Ahima RS, Flier JS. Leptin and the regulation of body weight. Nature. 2000;404(6778):656–60. PMID: 10766253.
2. Sharma D, et al. Role of leptin in reproductive function. Hum Reprod Update. 2013;19(3):297–312. PMID: 23478370.
3. Jéquier E. Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci. 2002;967:379–88. PMID: 12079866.
4. Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab. 2003;88(6):2404–11. PMID: 12788841.
5. Li Y, et al. Central GLP-1 receptor signalling accelerates leptin transport across the blood-brain barrier. J Clin Invest. 2011;121(2):446–457. PMID: 21206087.
6. Colberg SR, et al. Exercise and type 2 diabetes: American College of Sports Medicine and the American Diabetes Association joint position statement. Diabetes Care. 2010;33(12):e147-e167. PMID: 21115758.
7. Taheri S, et al. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med. 2004;1(3):e62. PMID: 15602591.
8. Kong W, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004;10(12):1344–51. PMID: 15531889.
9. Mori TA, et al. Dietary fish as a major component of a weight-loss diet: effect on serum lipids, glucose, and insulin metabolism in overweight hypertensive subjects. Am J Clin Nutr. 1999;70(5):817–25. PMID: 10539748.