Phenotype-Based Strategies for Better Weight Loss Outcomes


Weight loss resistance can be frustrating, but it’s often less about willpower and more about understanding how your body works. Recent research highlights how categorizing individuals into four distinct obesity phenotypes and tailoring interventions accordingly can significantly improve outcomes. 


Tailored Interventions Show Greater Success for Weight Loss

Personalized, phenotype-tailored interventions may result in greater weight loss compared to standard approaches, regardless of whether the intervention is pharmacological or focused solely on diet and lifestyle. 


Evidence from two studies underscores this point: one demonstrated the benefits of tailoring drug therapy, while the other highlighted the success of a non-pharmacological lifestyle program. In fact, participants in that study (Lancet, 2023) were excluded if they used medications known to influence body weight. 


Phenotype-guided obesity pharmacotherapy (Obesity, 2021): “the proportion of patients who lost >10% at 12 months was 79% in the phenotype-guided group compared with 34% with the non-phenotype-guided treatment group.” DOI: 10.1002/oby.23120.


Phenotype-tailored lifestyle intervention (Lancet, 2023): Participants in the tailored program experienced greater reductions in weight, waist circumference, fat mass, gastric emptying, anxiety, and triglycerides. They also gained more lean muscle and maintained better resting energy expenditure (REE). DOI: 10.1016/j.eclinm.2023.101923.  


These findings emphasize the value of customizing weight loss approaches to individual needs for improved outcomes in both drug-based and diet/lifestyle interventions.


Let’s explore what these phenotypes are, how they impact weight loss, and what steps you can take to support your weight loss goals.


Understanding the Phenotypes

As you’re reading, consider which phenotype best describes you and your weight loss challenges. If two or more phenotypes of obesity resonate, a combination approach may be needed to target the underlying mechanisms within each one. If that’s overwhelming, start with the most dominant one.


Please be aware that phenotype assessment and identification in a research setting is an extensive process. Clinically available tests and validated questionnaires were used in a rigorous and well controlled manner to capture key energy balance variables. The following sections titled "Quick Self-Assessment Tool" are not meant to replace that process.


Hungry Brain (Abnormal Satiation)

People in this group struggle with recognizing fullness cues, which leads to overeating.

  • Quick Self-Assessment Tool: Do you often eat quickly, eat until overly full, or crave large portions?
  • Intervention: Focus on high-fiber, high-water foods that promote fullness and eat slowly to enhance brain-gut feedback. Intermittent fasting may also help reduce caloric intake by shrinking eating windows.
  • Action Steps:
  • Focus on high-fiber, high-water content foods including a wide variety of colourful non-starchy vegetables.
  • Practice mindful eating: slow down, chew thoroughly, and pay attention to your body’s signals.
  • Structured meal timing, including two macronutrient balanced meals per day, with an optional second serving of vegetables per meal, as needed.
  • How to build a balanced meal: Precision Nutrition's Balanced Plate (page 1).
  • Dietary intervention used in the 2023 Lancet study: high fiber, low calorie diet with 1 to 2 meals a day. DOI: 10.1016/j.eclinm.2023.101923.  


Supporting Fullness to Control Hunger

Some individuals struggle with feeling full after eating, which can lead to overeating. This intervention was designed to help "switch off" hunger signals by minimizing the window for eating and focusing on a volumetric diet—meals structured to fill the stomach with high-volume, low-calorie foods. A second servings of fruits or vegetables to enhance fullness was offered to the participants, if desired.


Emotional Hunger (Hedonic Eating)

This group has a tendency to turn to food for emotional comfort or stress relief, leading to overeating.

  • Quick Self-Assessment: Do you reach for food when stressed, bored, or sad? Are cravings for sweets, salty snacks, or comfort foods a challenge for you?
  • What to Do: Behavioral approaches like mindfulness, emotional regulation strategies, and self-monitoring can help raise awareness of emotional eating patterns. 
  • Action Steps:
  • Avoid keeping trigger foods at home or within reach.
  • Structure meals to include nutrient-dense, balanced foods to minimize hunger and cravings.
  • Work on emotional regulation techniques like mindfulness, meditation, or journaling to address the root of emotional eating.
  • Use self-monitoring tools to track and identify patterns.
  • Dietary intervention used in the 2023 Lancet study: participants were instructed to follow a Mediterranean diet and to avoid snacks. DOI: 10.1016/j.eclinm.2023.101923.


Managing Emotional Eating with Mindfulness

This eating pattern often stems from negative moods, high anxiety, and reward-seeking behaviours to help regulate emotions. Given the strong connection to emotional eating, this intervention focused on improving emotional regulation without food. It included strategies like goal-setting, self-monitoring, and managing triggers to foster healthier coping skills and reduce emotional eating behaviors.


Hungry Gut (Abnormal Satiety)

People in this group feel hungry soon after meals due to rapid gastric emptying or imbalanced meals.

  • Self-Assessment: Do you feel hungry within an hour or two of eating? Do you struggle to stay full despite eating a complete meal?
  • What to Do: Eat protein-rich meals with adequate fiber and healthy fats to slow gastric emptying and prolong satiety. Avoid skipping meals or erratic eating patterns. 
  • Action Steps:
  • Emphasize protein preloads: eating protein-rich foods like tofu, lentils, or eggs before meals to extend satiety.
  • Structure meals around protein, fiber, and healthy fats to slow digestion.
  • Avoid skipping meals and ensure meal timing is consistent to regulate hunger hormones.
  • Dietary intervention used in the 2023 Lancet study: participants were instructed to have three meals per day with a pre-meal protein supplement. The intervention’s purpose was to deliver protein preloads to increase the early release of gastrointestinal hormones, and delay gastric emptying. DOI: 10.1016/j.eclinm.2023.101923.


Curbing Hunger with Protein Timing

Some individuals experience faster digestion and increased hunger after meals, leading to overeating. This intervention used protein preloads—small protein-rich portions consumed before meals—to trigger early release of hormones that impact digestion. This helps delay stomach emptying, keeping you fuller for longer and reducing post-meal hunger.


Slow Burn (Decreased Metabolic Rate)

This group struggles with a slower resting metabolic rate and reduced lean muscle mass.

  • Self-Assessment: Do you struggle to lose weight despite a calorie deficit? Do you have low muscle mass or difficulty maintaining energy levels?
  • What to Do: Resistance training to build muscle and boost metabolic rate, along with protein-rich diets to preserve lean mass. 
  • Action Steps:
  • Incorporate resistance training or strength-based exercises to build muscle and improve resting energy expenditure.
  • Ensure adequate protein intake to support muscle recovery and prevent loss of lean mass.
  • Stay active throughout the day by aiming for 10,000 steps daily or engaging in other physical activities like yoga or walking.
  • Dietary & Lifestyle interventions used in the 2023 Lancet study: participants were instructed to follow a Mediterranean diet, plus a post-work-out protein supplementation and to engage in at least 30 min of high-intensity interval training four to five times per week, with a weekly check-in with their physical therapist. DOI: 10.1016/j.eclinm.2023.101923.


Boosting Metabolic Rate with Muscle Mass

Some people naturally burn fewer calories at rest due to lower muscle mass, which can lead to weight gain over time. Since muscle is the most active part of the body for burning energy, this intervention focused on building lean muscle through structured exercise. It included high-intensity resistance training to strengthen and grow muscles, paired with a protein supplement after workouts to support muscle development. These steps were designed to increase overall energy expenditure.


Tailored Interventions Show Greater Success for Weight Loss

Weight loss resistance is often frustrating, but it’s not just about willpower or calorie counting—it's about understanding the unique physiology driving your body’s responses. 


In both studies, the phenotype-guided treatment group achieved significantly better weight loss outcomes compared to the non-phenotype-guided group. This raises an important question: Could these findings help explain why individuals respond so differently to obesity treatments like specific diets, medications, or even surgical interventions? 


Understanding and addressing these unique physiological differences might hold the key to more effective and sustainable weight loss strategies.


The Benefits of Personalized Weight Loss Strategies

By understanding which phenotype matches your challenges, you can adopt specific strategies that work for your body. This tailored approach not only helps overcome weight loss resistance but also:


  • Improves the effectiveness of medications, diet and lifestyle changes by addressing the underlying causes of overweight and obesity.
  • Reduces frustration by eliminating trial-and-error methods. A phenotype-tailored approach is designed to predict best responders for both drug-based and diet/lifestyle interventions.
  • Leads to better outcomes on weight loss, cardiometabolic risk factors and physiologic variables contributing to obesity pathophysiology.


Takeaways

Weight loss isn’t a one-size-fits-all journey. Your body is unique, and your weight loss plan should reflect that. Phenotyping for obesity moves us beyond general weight loss advice. It ensures interventions are not only evidence-based but also personalized for the individual’s unique metabolic and behavioral profile. 


Although more research is needed, these studies illustrate the complexity of weight loss and provide an explanation for the varied responses to obesity interventions. 


Take time to identify your challenges, implement targeted strategies, and work toward health.

References


Acosta A, Camilleri M, Abu Dayyeh B, et al. Selection of Antiobesity Medications Based on Phenotypes Enhances Weight Loss: A Pragmatic Trial in an Obesity Clinic [published correction appears in Obesity (Silver Spring). 2021 Sep;29(9):1565-1566. doi: 10.1002/oby.23236] [published correction appears in Obesity (Silver Spring). 2022 Jul;30(7):1521. doi: 10.1002/oby.23498]. Obesity (Silver Spring). 2021;29(4):662-671. doi:10.1002/oby.23120


Phenotype tailored lifestyle intervention on weight loss and cardiometabolic risk factors in adults with obesity: a single-centre, non-randomised, proof-of-concept study Cifuentes, Lizeth et al.eClinicalMedicine, Volume 58, 101923