There is no strong evidence that any specific diet is the preferred treatment for lipodystrophy syndromes. Here we remark on the benefits of a very-low-calorie diet (VLCD) in a patient with familial partial lipodystrophy type 2 (FPLD2). A 38-year-old female diagnosed with FPLD2, with a history of multiple comorbidities, underwent 16 weeks of VLCD with a short-term goal of improving her metabolic state rapidly to achieve pregnancy by in vitro fertilization (IVF). We observed a reduction of 12.3 kg in body weight and 1.4% in hemoglobin A1c. The decrease in the area under the curves of insulin (−33.2%), triglycerides (−40.7%), and free fatty acids (−34%) were very remarkable. Total body fat was reduced by 16%, and liver fat by 80%. Her egg retrieval rate and quality during IVF were far superior to past hyperstimulation. Our data encourage the use of this medical approach for other patients with similar metabolic and reproductive abnormalities due to adipose tissue insufficiency.

Lipodystrophy syndromes are a heterogeneous group of rare genetic or acquired disorders characterized by generalized or partial loss of adipose tissue which causes insulin resistance, ectopic steatosis, and hypertriglyceridemia [1]. Familial partial lipodystrophy type 2 (FPLD2) is a form of monogenic lipodystrophy caused by heterozygous and rarely compound heterozygous variants in the LMNA gene encoding lamins A and C [2, 3]. Laminopathies impact the structural organization, stabilization, and replication of almost all cells, leading to different clinical phenotypes [4].

Patients with FPLD2 show progressive fat redistribution beginning around puberty, as they lose fat from the trunk, limbs, and buttocks while gaining fat in the face, neck, axillae, and visceral organs [5]. Diagnosis of the clinical phenotype with accompanying hormonal and metabolic derangements is critical for reducing the increased risk of organ involvement, which may lead to serious complications, including cardiovascular disease, cirrhosis, and pancreatitis, among others [5, 6]. Female patients are more severely affected than males [7]. Reproductive abnormalities are common with complications that may even extend to the fetus, resulting in impaired embryonic development and decreased viability [8, 9].

There is currently no treatment available for partial lipodystrophy syndromes in the USA; general measures are based on exercise and a balanced [2] diet. While metreleptin is the only drug approved specifically for generalized lipodystrophy in the USA [1, 5], its use in certain conditions, such as preconception or pregnancy, is still controversial [5, 10].

Although diet is the primary intervention, there are no guidelines and insufficient evidence to recommend any specific dietary approach [1, 5, 11]. Very-low-calorie diet (VLCD) (≤800 kcal/day) has been shown to have beneficial pleiotropic effects, including on glucose and lipid metabolism in individuals with obesity, even with reports of remission in patients with type 2 diabetes [12, 13]. However, there is no research on the use of a VLCD in patients with FPLD2. We report the effect of this aggressive calorie-restricted diet in a patient with FPLD2 who showed remarkable benefit after 16 weeks of the intervention. The intervention was chosen due to the need to intervene quickly and with the understanding that FPLD2 patients can still show signs and symptoms of nutritional overload despite relatively normal body mass index (BMI) ranges.

A 38-year-old female patient who has been following with us intermittently for her diagnosis of FPLD2, carrying a missense variant in LMNA gene p.(Arg482Gln), was referred from the infertility clinic with a short-term goal of improving her metabolic state rapidly to achieve pregnancy by in vitro fertilization. She had previous attempts at ovarian stimulation, egg retrieval, and embryo transfer. Medical history showed that she had recurrent pancreatitis dating back to 9 years of age, nonalcoholic fatty liver disease, and a 3-year history of what was labeled as type 2 diabetes. She also had partial pancreatectomy (distal 40% of her pancreas) and splenectomy due to complications from recurrent pancreatitis. She was being treated with multiple daily insulin injections (0.8 IU/kg/day) and gemfibrozil. On baseline examination, she had a weight of 81.6 kg and BMI of 23.2 kg/m2. She had increased accumulation of adipose tissue around the neck, in supraclavicular area, prominent submental fat pads, broad shoulders, muscular arms, and legs with reduced subcutaneous fat. Upon presentation, she had diabetes with hemoglobin A1c (HbA1c) of 7.7% and dyslipidemia with a triglyceride level of 215 mg/dL. There was evidence of insulin resistance and preserved C-peptide secretion (Table 1; Fig. 1). Her diabetes-related antibody screen was negative.

Table 1.

Effects of VLCD intervention at baseline and 16 weeks after treatment

BaselinePosttreatment% change
Body weight, kg 81.6 69.1 −15 
BMI, kg/m2 32.2 27.1 −15 
HbA1c, % 7.7 6.3 −18 
Total cholesterol, mg/dL 191 175 −8 
HDL, mg/dL 43 39 −9 
Triglyceride, mg/dL 215 134 −37 
LDL, mg/dL 124 117 −5 
ALT, IU/L 28 22 −21 
AST, IU/L 22 23 
ALP, IU/L 73 77 
GGT, IU/L 13 −38 
BUN, mg/dL 17 15 −11 
Glucose, mg/dL 96 88 −8 
Insulin, µU/mL 21.5 7.7 −64 
C-peptide, ng/mL 1.5 1.1 −3 
Fasting FFA, mmol/L 0.8 0.8 −2 
Glucose AUC, mg/dL/min 40,695 39,300 −3 
Insulin AUC, mcU/mL/min 11,231 7,497 −33 
Trigs AUC, mg/dL/min 39,720 23,565 −40 
C-peptide AUC, mg/L/min 1,851 1,761 −4 
FFA AUC, mmol/L/min 67 44 −34 
HOMA-IR 5.1 1.7 −66 
ADIPO-IR 2.38392 0.8316 −65 
Total body fat, g 21,692 14,695 −32 
Total lean mass, g 57,084 52,129 −8 
BaselinePosttreatment% change
Body weight, kg 81.6 69.1 −15 
BMI, kg/m2 32.2 27.1 −15 
HbA1c, % 7.7 6.3 −18 
Total cholesterol, mg/dL 191 175 −8 
HDL, mg/dL 43 39 −9 
Triglyceride, mg/dL 215 134 −37 
LDL, mg/dL 124 117 −5 
ALT, IU/L 28 22 −21 
AST, IU/L 22 23 
ALP, IU/L 73 77 
GGT, IU/L 13 −38 
BUN, mg/dL 17 15 −11 
Glucose, mg/dL 96 88 −8 
Insulin, µU/mL 21.5 7.7 −64 
C-peptide, ng/mL 1.5 1.1 −3 
Fasting FFA, mmol/L 0.8 0.8 −2 
Glucose AUC, mg/dL/min 40,695 39,300 −3 
Insulin AUC, mcU/mL/min 11,231 7,497 −33 
Trigs AUC, mg/dL/min 39,720 23,565 −40 
C-peptide AUC, mg/L/min 1,851 1,761 −4 
FFA AUC, mmol/L/min 67 44 −34 
HOMA-IR 5.1 1.7 −66 
ADIPO-IR 2.38392 0.8316 −65 
Total body fat, g 21,692 14,695 −32 
Total lean mass, g 57,084 52,129 −8 

Metabolic parameters before and 16 weeks after treatment.

BMI, body mass index; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; BUN, blood urea nitrogen; FFA, free fatty acids; AUC, area under the curve; HOMA-IR, homeostatic model assessment–insulin resistance; ADIPO-IR, adipose tissue insulin resistance.

Fig. 1.

Changes in body fat composition before and after treatment. a Fat shadows showing the reduction of fat with treatment. Panel on the left shows baseline state (total fat percentage 27.5%, fat mass ratio [FMR] 3.3), while the panel on the right shows the baseline state 16-week post-intervention (total body fat percentage 22%, FMR 3.2). Fat mass ratio was obtained by dividing trunk fat mass (g)/legs fat mass (g). Note that yellow coloring highlights the “Fat shadow” and these images are useful for appreciating the extent of residual fat and sufficient to demonstrate fat loss with intervention. b Curves from oral glucose tolerance test with 75 g of glucose for 180 min after glucose load both before and 16 weeks of posttreatment. Data for insulin, glucose, triglycerides, and free fatty acids are shown. c Magnetic resonance imaging-derived fat percentages of the liver as measured via chemical shift (Dixon) method before (left, 10 ± 2% fat in the liver) and 16 weeks after treatment (right, 2 ± 2% fat in the liver), shown on 0–20% fat-fraction color scale.

Fig. 1.

Changes in body fat composition before and after treatment. a Fat shadows showing the reduction of fat with treatment. Panel on the left shows baseline state (total fat percentage 27.5%, fat mass ratio [FMR] 3.3), while the panel on the right shows the baseline state 16-week post-intervention (total body fat percentage 22%, FMR 3.2). Fat mass ratio was obtained by dividing trunk fat mass (g)/legs fat mass (g). Note that yellow coloring highlights the “Fat shadow” and these images are useful for appreciating the extent of residual fat and sufficient to demonstrate fat loss with intervention. b Curves from oral glucose tolerance test with 75 g of glucose for 180 min after glucose load both before and 16 weeks of posttreatment. Data for insulin, glucose, triglycerides, and free fatty acids are shown. c Magnetic resonance imaging-derived fat percentages of the liver as measured via chemical shift (Dixon) method before (left, 10 ± 2% fat in the liver) and 16 weeks after treatment (right, 2 ± 2% fat in the liver), shown on 0–20% fat-fraction color scale.

Close modal

This study was reviewed and approved by the Ethical Committee of the University of Michigan (IRB Med approval number: LD-LYNC HUM#00127427) and performed according to the principles of the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Diet Intervention

She was started on VLCD (800 kcal/day) with a total formula liquid diet meal replacement comprising: 160 kcal per shake (18 g total carbohydrates, 15 g net carbohydrates, 3.5 g fat, and 16 g protein) with the goal to reduce body weight by 15% as has been described for patients in the University of Michigan Weight Management Program [14]. Twelve weeks of VLCD were followed by 4 weeks of low-calorie diet (incorporating 3 meal replacements and 1 meal with ad libitum non-starchy vegetables). Before and after the intervention, the patient underwent an oral glucose tolerance test (OGTT) with 75 g of glucose for 180 min and body fat distribution evaluation by dual-energy X-ray absorptiometry scan [15] and liver fat measurements via the chemical shift magnetic resonance imaging method (also referred to as Dixon method) [16].

After 1 week on diet, she discontinued both glucose- and lipid-lowering treatments. After the 16-week intervention, we observed 12.3 kg of body weight reduction and 1.4% decrease in HbA1c (Table 1). Insulin resistance was reduced when evaluated by homeostatic model assessment of insulin resistance (HOMA-IR) and adipose tissue insulin resistance (ADIPO-IR) by 66% and 65%, respectively (Table 1). Fasting insulinemia was reduced by 64.2% (Table 1). Total body fat was reduced by 32%, while body lean mass has a slight reduction of only 8% (Table 1). Dual-energy X-ray absorptiometry scan showed a reduction of 16% in total body fat (Fig. 1a). OGTT showed a decrease in the area under the curve on all parameters evaluated but more significantly on insulin (−33.2%), triglycerides (−40.7%), and free fatty acids (−34%) (Fig. 1b). The chemical shift magnetic resonance imaging method demonstrated that liver fat was reduced from 10 ± 2% to 2 ± 1% (Fig. 1c). Her egg retrieval rate and quality during hyperstimulation prior to in vitro fertilization were far superior to past attempts and were noted to increase from 15 to over 40 follicles. She did not experience any adverse events during the intervention.

This case illustrates the robust and safe effect of VLCD in a patient with lipodystrophy. We propose that this intervention may be considered as a medical approach, particularly in women wanting to achieve pregnancy more urgently. In addition, this experience confirms that aggressive calorie restriction may be an effective treatment strategy even when there is deficiency of adipose tissues as the residual adipose compartments may still exhibit over-engorgement, and this can, in turn, contribute to the metabolic disease. The VLCD may enable a break in this metabolic vicious cycle, albeit transiently.

Given the rarity of lipodystrophy syndromes, dietary recommendations on energy restrictions or very-low-fat diets for ameliorating metabolic derangements are based on clinical experience rather than evidence [1, 11]. Without guidelines, patients are advised to follow an unspecified calorie restriction comprised 50–60% carbohydrate, 20–30% fat, and 20% protein [1]. With our VLCD, not only were calories limited, but the composition generally recommended was different [1]. The prescribed diet consisted of 63% carbohydrate, 7% fat, and 30% protein. In parallel with the general recommendation for hypertriglyceridemia, her diet was very low in fat [1] but had a relatively higher ratio of protein-to-carbohydrates. That said, the total amount of protein in her diet was lower than what was consumed in her ordinary diet and in line with the general recommendations on lowering protein supplementations to improve metabolic syndromes [17].

After only 1 week on VLCD, insulin and gemfibrozil were discontinued, the diet showed an immediate effect on glucose and lipid metabolism. Reductions in blood glucose, HbA1c, triglycerides, and fatty acids were indicative of her metabolic improvement, which was quantified by assessments of her total body and liver fat. Notably, the effects were comparable to those observed with metreleptin treatment in generalized lipodystrophy [18].

It is particularly important to highlight that the relationship between the metabolic derangements and BMI levels of patients with FPLD is distinct from those individuals with obesity [19]. We have previously demonstrated that BMIs of patients with FPLD matched for metabolic control of individuals with obesity were 6.5–10.7 kg/m2 higher [19]. Hence, the metabolic burden or control of these patients should not be underestimated or managed solely based on their BMIs. Our results highlight that efforts to try to reduce excess nutrients on board may still provide substantial benefit, though it may be hard to achieve over the long term.

Based on our experience, we believe that more stringent dietary restrictions can be implemented for certain circumstances in lipodystrophy syndromes. LMNA variants have been associated with premature cell aging and have been reported to affect various cells in the body, including myoblasts, cardiomyocytes, adipocytes, and endothelial vascular cells [4]. Harboring the most common pathogenic LMNA variant, R482W [3], which is hypothetically detrimental to almost all vital cells, our patient had been suffering from life-threatening metabolic complications for over 30 years. As demonstrated by the clinical improvement of our patient after VLCD, certain periods of a VLCD intervention could be sufficient in safely restoring the metabolic regulation in severe phenotypes of lipodystrophy.

Given the unique challenges of preconception and pregnancy, VLCD may be particularly important among this specific group. Hypoleptinemia affects the pulsatility of the hypothalamic-pituitary-gonadal axis, downstream of which results in hyperandrogenemia such that the reproductive problems in severe phenotypes seem inevitable [4, 8, 20]. Yet, the data on fertility in patients with FPLD2 are scarce [8, 10]. In a series of 14 female patients, 28% had infertility, and none with prepregnancy diabetes were able to conceive spontaneously, as was the case with our patient [8]. With the lack of recommendations regarding the safety of metreleptin during preconception and pregnancy, this dietary approach may be an acceptable option [1, 10]. Whether VLCD might be a successful intervention in all patients with lipodystrophy and how to sustain beneficial effects of reduced calorie state in the longer term both require further studies.

Our data encourage the use of a monitored VLCD for patients with similar metabolic and reproductive abnormalities due to loss of adipose tissue and abnormal distribution.

The authors thank the patient for allowing to report her unique case.

This study was reviewed and approved by the Ethical Committee of the University of Michigan (IRB Med approval number: LD-LYNC HUM#00127427) and performed according to the principles of the Declaration of Helsinki. Written informed consent was obtained from the patient for publication of this case report and accompanying images.

E.A.O. has received grant support and/or consultancy fees from Aegerion Pharmaceuticals, Akcea Therapeutics, Ionis Pharmaceuticals, Regeneron Pharmaceuticals, Gemphire Therapeutics, Novo Nordisk, Rhythm Pharmaceuticals, and GI Dynamics. She also served as an advisor to the first 4 companies and has royalty rights from the use of metreleptin in lipodystrophy. All other researched do not conflicts of interest to declare.

This study was supported by a grant from the NIDDK (NIH Grant No. 1R01DK125513). This work utilized Core Services supported by grant DK089503 to the University of Michigan.

M.F.F. collected and analyzed the metabolic and clinical data and wrote a draft of the manuscript. O.B. researched data, contributed to the discussion, and wrote another draft. A.N. and RM collected the data. T.L.C. analyzed and collected data. E.A.O. and A.E.R. conceived the intervention for this patient, oversaw the data collection and analysis, and reviewed and edited the manuscript. A.E.R. conducted the dietetic intervention and reviewed and edited the manuscript. All authors approved the final version of the manuscript. E.A.O. is the guarantor of this work, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Additional Information

Elif A. Oral and Amy E. Rothberg contributed equally to this work and are the joint senior authors for this manuscript. The abstract was presented at the ENDO Society Annual Meeting (ENDO) conference in June 2022.

Deidentified data are available under request with proper justification to the corresponding author. Data are not publicly available due to ethical reasons. Further inquiries can be directed to the corresponding author.

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