A 59-year-old woman sat tearfully in my office today. She had spent seven weeks on tirzepatide with virtually no weight loss. “How is this possible?” she asked. “I’m eating like a saint.”
She had struggled with obesity and weight-related frustration for years. Recently divorced, grieving a death in the family, caring for a mentally ill adult daughter, working full time, sleeping poorly, and living with severe anxiety, she described her stress level as “10 out of 10.” Like many women in midlife, she had spent years carrying the weight of everyone else’s needs while functioning in a near-constant state of physiologic overdrive.
We carefully reviewed her food diary together. She was NOT surviving on fast food or nightly binge eating. She was eating predominantly whole foods, low carbohydrate, virtually no sugar, lean proteins, approximately 100-120 grams of protein daily, drinking close to 100 ounces of water per day, and averaging roughly 1,200-1,400 calories daily. She was making a genuine effort and following recommendations more diligently than many patients ever do.
And yet, the dominant cultural narrative around obesity still often reduces weight loss to some version of “eat less, move more, take the medication.”
Glucagon-like peptide-1 (GLP-1) and GLP/GIP medications such as semaglutide and tirzepatide have unquestionably transformed obesity medicine. For many patients, these medications are life-changing. But clinicians are increasingly encountering another reality as well: Some patients lose dramatic amounts of weight, while others lose very little or no weight despite substantial effort.
Medicine has spent decades framing obesity largely as a disorder of appetite and willpower. But increasingly, research suggests that obesity is also deeply neuroendocrine, inflammatory, psychiatric, behavioral, and social. Many patients are not simply overeating. Many are living under chronic allostatic load.
The physiologic stress response is mediated through both the autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. Acute activation of these systems is adaptive and necessary for survival. But when stress becomes chronic, prolonged sympathetic “fight or flight” activation and sustained cortisol signaling may contribute to insulin resistance, visceral adiposity, inflammation, disrupted sleep, altered appetite regulation, impaired energy expenditure, and broader metabolic dysfunction. In some individuals, this physiologic survival response may contribute to increasing resistance to weight loss despite significant dietary effort. Importantly, this does not mean calories no longer matter or that obesity can be reduced to cortisol alone. Human metabolism is vastly more complex than social media slogans from either side of the debate. But it may help explain why some individuals struggle profoundly despite seemingly “doing everything right.”
The body is not a static calorie calculator. Under chronic stress, neuroendocrine adaptation occurs. Sleep deprivation alters leptin and ghrelin signaling. Chronic cortisol exposure may promote visceral adiposity and insulin resistance. Inflammatory cytokines interact with metabolic pathways. Caloric restriction itself can function as a physiologic stressor in some individuals. Adaptive thermogenesis may reduce energy expenditure during sustained weight loss efforts.
In other words, some bodies become biologically organized around conservation and survival. From an evolutionary standpoint, this physiologic survival response made sense during famine, scarcity, and prolonged threat. Helpful for surviving conditions closer to Stalin-era deprivation than modern American life. The challenge is that while our environment has radically changed, human stress physiology remains remarkably conserved, and many nervous systems still respond to chronic psychological stress as though survival itself is under threat.
This may be especially relevant in women navigating midlife hormonal shifts alongside chronic caregiving demands and psychiatric burden. Many of these patients are exhausted long before they arrive at an obesity clinic.
Yet many treatment models often remain narrowly focused on appetite suppression. GLP-1 medications are powerful tools. But they may work best when combined with broader attention to sleep quality, nervous system regulation, psychiatric illness, trauma, inflammatory contributors, nutrient/protein intake, metabolic health, and sustainable behavioral change.
In psychiatry, we routinely recognize that the brain and body cannot be separated. Obesity medicine may increasingly require the same lens.
Perhaps the future of obesity treatment is not simply stronger appetite suppression, but a deeper understanding of why so many bodies no longer feel physiologically safe enough to let the extra weight go.
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This essay is cited in the KevinMD record on GLP-1 drugs.
Carrie Friedman is a dual board-certified psychiatric and family nurse practitioner and the founder of Brain Garden Psychiatry in California. She integrates evidence-based psychopharmacology with functional and integrative psychiatry, emphasizing root-cause approaches that connect neuro-nutrition and gut–brain science, metabolic psychiatry, immunology, endocrinology, and mind–body lifestyle medicine. Carrie’s clinical focus bridges conventional psychiatry with holistic strategies to support mental health through nutrition, physiology, and sustainable lifestyle interventions. Her professional writing explores topics such as functional medicine, autism, provider well-being, and medical ethics.
