. 2021 Nov 24;12:749050. doi: 10.3389/fendo.2021.749050

Table 2.

Summary of studies linking nutritional interventions to decrements in leptin concentration*.

Study	Study Characteristics	Main intervention	Main results^a
Boden G, et al. (54)	- 5 individuals (age 42.2 ± 5.8 y, 2 men and 3 women) with BMI <28 kg.m². - 5 individuals (age 35.6 y ± 6.7 y, 2 men and 3 women) with BMI >28 kg.m².	- Total fast (0 kcal, 52 hours).	- Serum leptin decreased by 64% in individuals with BMI <28 kg.m². - Serum leptin decreased by 72% in individuals with BMI >28 kg.m².
Mars M, et al. (55)	- 34 healthy men (age 23 ± 3 y) with average BMI 22.3 ± 1.6 kg.m².	- 2 days, 62% energy restriction. - With 55% energy from carbohydrates, 20% fat, and 25% protein. - Food ad libitum after intervention.	- Leptin concentration decreased by 27.2%. - Decrements in leptin concentration: not associated with changes in body weight (r=0.20, P>0.05) or insulin concentrations (r=0.21, P>0.05), but highly associated with fasting leptin concentrations at baseline (r=0.89, P<0.0001), the proportion of energy restriction (r=0.48, P<0.01), and baseline body mass index (r=0.44, P<0.01), as well as weakly associated with baseline body weight (r=0.33, P=0.05). -Leptin concentration increased by 37.6% on day 5 (uncontrolled diet).
Mars M, et al. (56)	- 44 healthy men (age 43 ± 5 y with BMI 27.3 ± 3.2 kg.m²).	- 4 days, 65%-energy-restricted diet. - With 26% energy from protein, fat 19%, and carbohydrates 55%.	- Leptin concentration declined by 39.4%. - Decrement was associated with an increase in fasting hunger (r=0.42, P<0.01), desire to eat (r=0.39, P<0.05) and total appetite (r=0.38, P<0.05). - Higher absolute (not relative) reduction in individuals with obesity (-4.1 ng/ml) or who were overweight (-1.5 ng/ml) than in participants with BMI <25 kg.m² (2.2 ng/ml).
Wisse BE, et al. (57)	- 21 women with obesity (age 41 ± 3 y, weight: 102 ± 4 kg, 48 ± 1% body fat).	- Group 1: total fast. - Group 2: All-protein, very-low-energy diet (≈455 kcal). - Group 3: Low-energy, balanced-deficit diet (50% maintenance energy). - One week of refeeding with the diet of group 3.	- Leptin levels significantly decreased in the 3 groups at week 1 (up to 66%). - These decrements continued through week 4, though less significantly. - There were greater declines in leptin associated with greater energy deficits. - Decrease in leptin in group 3 was significantly lower than in group 1 from weeks 1 to 4 (P=0.026). - By the end of week 5 (refeeding), leptin increased significantly (P=0.002) in group 1.
Wadden TA, et al. (58)	- 49 women with obesity (age 45.0 ± 9.6 y with BMI 36.4 ± 4.5 kg.m²).	- A 40-week weight loss program. - Group 1 (low-calorie diet): 1000 kcal/day (weeks 2–13); 1200 kcal/day, with 12–15% energy from protein, 55–60% carbohydrates, and 25–30% fat (by week 17); 1200–1800 kcal/day (weeks 21–40). - Group 2 (balanced-deficit diet): usual food intake in first week; 1200 kcal/day, with 12–15% energy from protein, 55–60% carbohydrates, and 25–30% fat (weeks 2–20); 1200–1800 kcal/day (weeks 21–40).	- Leptin decreased more at weeks 6 and 10 in group 1 than in group 2 (P<0.05). - At week 10, leptin decreased by 53.0 ± 18.2% in group 1 and 33.2 ± 23.3% in group 2. - Caloric restriction accounted for 14% of the variance in leptin changes at week 6; weight loss did not add significantly to this variance. - At week 10, diet (21%) and weight loss accounted for 36% of the variance in leptin changes. - Week 40: Leptin concentration in group 1 decreased by 37.4 ± 25.9% and ≈35% in group 2.
Varkaneh HK et al. (59)	- 12 studies with 17 arms and a total of 495 women and men (intervention = 249, control = 246).	Fasting and energy-restricted diets and their subgroups: - Energy intake limited to ≤50% of normal energy intake. - Energy restriction regiments with >50% of normal energy intake. - Alternate-day fasting. - Intermittent fasting.	- Overall, leptin levels significantly declined (WMD: -3.69 ng/ml, 95% CI: -5.19, -2.19, P ≤ 0.001). - Energy-restricted diets only: WMD = -5.23 ng/ml, 95% CI: -7.96, -2.50. - Fasting regimens only: WMD = -2.56 ng/ml, 95% CI: -4.86, -0.25. - Energy intake limited to ≤50% of the normal required daily energy intake: WMD = -4.20 ng/ml, 95% CI: -7.28, -1.12. - Alternate day fasting: WMD = -14.37 ng/ml, 95% CI: -24.03, -4.72. - No statistically significant changes associated with energy restriction regiments with >50% of normal energy intake and intermittent fasting interventions. - Interventions lasting ≥12 weeks: WMD: = -6.92 ng/ml, 95% CI: -10.46, -3.37. - Interventions lasting <12 weeks: WMD = -2.05 ng/ml, 95% CI: -3.54, -0.55. - BMI ≥25 kg.m² at baseline: WMD: = -8.11 ng/ml, 95% CI: -11.97. - BMI <25 kg.m² at baseline: WMD: -1.35 ng/ml, 95% CI: -2.36, -0.35.

*Lowering leptin levels has been proposed as a potential intervention to normalize the sensitivity of this hormone. Studies focused on fasting and energy-restricted diets.

^aStatistical measures presented in this table are heterogeneous since they are shown as they were available in the reviewed studies.

BMI, body mass index; WMD, weighted average mean.