Leptin’s Role in Lipodystrophic and Nonlipodystrophic Insulin-Resistant and Diabetic Individuals

394 Moon et al Effects of Leptin on Glucose Metabolism Endocrine Reviews, June 2013, 34(3):377–412
domized and not placebo-controlled and its study participants
continued to use their lipid-lowering regimens
during leptin treatment. Recent results from a small randomized,
double-blinded, placebo-controlled clinical trial
indicate that leptin administration improves glycemia and
non-HDL cholesterol levels to some extent but cannot
ameliorate lipid kinetics in adults with HIV-associated
dyslipidemic lipodystrophy, providing a mechanistic reasoning
behind the inconsistent effect of leptin on lipid profiles
(237). Specifically, metreleptin administration to hypoleptinemic
patients with HIV-associated dyslipidemic
lipodystrophy at doses that significantly elevate plasma
leptin levels does not ameliorate the markedly abnormal
fasting lipid kinetic defects characteristic of this condition,
ie, accelerated lipolysis and adipocyte and hepatic reesterification,
with blunted oxidative disposal of free fatty
acids (237). Conversely, recombinant human GH and human
GHRH, which present beneficial effects on lipid metabolism,
have been shown to improve visceral fat, TG,
and cholesterol levels but not glucose parameters in patients
with HALS, presenting also an unclear impact on
cardiovascular endpoint (238, 239).
Similar to leptin, hypoadiponectinemia is associated
with insulin resistance, hypertriglyceridemia, and adipose
tissue redistribution in patients with HALS (240–242).
Adiponectin administration has been demonstrated in animals
to improve insulin sensitivity and dyslipidemia (243,
244). Although adiponectin or leptin alone only partly
alleviate insulin resistance in mouse models of lipodystrophy,
the combined administration of both hormones fully
normalizes insulin sensitivity (244). Given that no synthetic
form of adiponectin is yet available for human use,
animal studies as well as studies on medications that indirectly
increase endogenous levels of adiponectin such as
thiazolidinediones, have highlighted adiponectin’s therapeutic
potential (245). We have found that pioglitazone, a
thiazolidinedione that increases adiponectin levels, may
have beneficial effects on HALS-associated insulin resistance.
Recently, we performed a randomized, doubleblinded
pilot study on the combined administration of
leptin and pioglitazone for 3 months in 9 HALS patients
(246). Compared with pioglitazone alone, combined
treatment reduced fasting serum insulin concentrations,
increased adiponectin concentrations, improved insulin
resistance (homeostasis model assessment [HOMA]), and
attenuated postprandial glycemia in response to a mixed
meal (246). These preliminary findings indicate that this
combination could further improve glycemic control and
needs to be replicated in larger and longer-term studies. If
confirmed and proven to be superior to the current standard
of care, the treatment of HALS in the future may
involve leptin replacement in conjunction with pioglitazone
and/or adiponectin. Figure 2 depicts the effect of
recombinant leptin administration in HALS.
4. Hypothalamic amenorrhea
Hypothalamic amenorrhea (HA) is a disorder characterized
by the cessation of menstrual cycles with anovulatory
infertility and moderate to severe hypoleptinemia,
usually caused by reduced food intake or chronic energy
deficiency secondary to strenuous exercise (204). Leptin
administration to lean women who are affected by this
disorder and undertake strenuous exercise resulted in
recuperation of reproductive outcomes, correction in
the gonadal, thyroid, GH, and adrenal axes, and improvements
in markers of bone formation (247–249).
Nonetheless, larger clinical trials are needed to confirm
the previous studies.
B. States of leptin excess
1. Common obese state
In contrast to the few obese subjects with congenital
leptin deficiency, most obese individuals exhibit greater
leptin concentrations than lean subjects due to their
greater amount of fat mass and are unresponsive to exogenous
leptin in terms of anorectic effects, body weight
reduction, and glycemic control, due to leptin resistance as
discussed in Introduction (22, 23) (Table 5). These results
reduced expectations from leptin-based antiobesity therapeutic
approaches.
Despite their shortcomings, mouse models with HFDinduced
obesity may provide important insights into understanding
the effects of leptin on glucose metabolism in
obese humans because these mouse models are the closest
to human obesity. Chronic infusion of leptin in C57BL/6J
mice on HFD did not improve the glucose response to
insulin during an insulin tolerance test, even though the
body weight of mice effectively decreased compared with
control mice (250). Moderate hyperleptinemia achieved
by adenovirus gene therapy somewhat improved glucose
tolerance in animals that had 4-fold greater leptin concentrations
compared with control rats (251). Therefore,
serum concentrations of leptin may be an important factor
responsible for the restoration of aberrant glucose metabolism
in HFD-induced obese animal models. Leptin administration
in other mouse models of obesity has shown
mixed results. Harris et al (252) found that leptin treatment
improved insulin resistance and hyperglycemia in
some strains of db/db mice, but the effects depended on sex
and mode of administration (chronic or bolus ip administration).
Other authors found no benefits of leptin administration
in db/db mice (5). Leptin treatment in a mouse model
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 10 June 2014. at 01:44 For personal use only. No other uses without permission. . All rights reserved.