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

doi: 10.1210/er.2012-1053 edrv.endojournals.org 379
quentlyinvisceralobesity(27).Table1depictsfactorsthat
affect circulating leptin levels in humans.
C. Leptin receptors
Leptin exerts its effects via binding to specific leptin
receptors (obese receptors [ObRs]) located throughout the
central nervous system (CNS), including the hypothalamus,
and several peripheral organs (4, 10, 28). The leptin
receptor is a receptor in the class 1 cytokine receptor family,
with a single membrane-spanning domain (10, 24, 28,
29). At present, 6 ObR isoforms, produced by alternative
splicing of the leptin receptor gene, have been identified in
rats (ObRa–ObRf) (30). In mice and humans, only 5
(ObRa–ObRe) and 4 (ObRa–ObRd) alternative spliced
isoforms have been described, respectively (30, 31). These
isoforms present homologous extracellular leptin-binding
domains but distinct intracellular domains varying in
length and sequence due to alternative mRNA splicing
(32). The short isoforms ObRa and ObRc may play an
important role in transporting leptin across the bloodbrain
barrier (BBB) (32).
The long leptin receptor isoform, ObRb, which contains
a full-length intracellular domain required for cell
signal transduction, is primarily responsible for leptin signaling
(30, 31, 33) (Figure 1). ObRb is strongly expressed
throughout the CNS and particularly in the hypothalamus,
where it regulates energy homeostasis (food intake
and energy expenditure) and neuroendocrine function
(30, 32–35). In the db/db mouse model, the ObRb is dysfunctional,
resulting in obesity and the metabolic syndrome
(36). ObRb mRNA is highly expressed in the hypothalamus,
particularly in the arcuate nucleus (ARC), the
ventromedial hypothalamus (VMH), the lateral hypothalamic
area, the dorsomedial hypothalamus (DMH), and
the ventral premammillary nucleus (32). Via its receptor,
leptin directly targets hypothalamic neurons, particularly
ARC neurons (proopiomelanocortin [POMC] and agoutirelated
protein [AgRP] neurons), which are critical mediators
of leptin action (37). POMC neurons are anorexigenic
(appetite suppressor) neurons coexpressing POMC
and cocaine- and amphetamine-regulated transcript. After
proteolytic cleavage, POMC generates -MSH, which
stimulates melanocortin-3 and -4 receptors (MC3R and
MC4R), which are important in energy homeostasis (37).
Genetic defects in the melanocortin system (POMC or
MCR genes) are related to obesity in humans (38). Conversely,
AgRP neurons are orexigenic (appetite stimulator)
neurons that inhibit POMC activity by releasing inhibitory
-aminobutyric acid and coexpress the orexigenic
AgRP and neuropeptide Y (NPY), antagonists of both
MC3R and MC4R (39). Leptin inhibits AgRP/NPY expression
and AgRP neuronal excitability as well as -aminobutyricacid
release from AgRP neurons (39). Moreover,
in the VMH, leptin stimulates the expression of anorexigenic
brain-derived neurotrophic factor (BDNF) through
MC4R signaling (40). Finally, in the hypothalamus, leptin
acts on neurons that directly or indirectly regulate levels of
other circulating hormones (eg, thyroid hormone, sex steroids,
and GH) (30, 32, 33, 41). Leptin action on these
hypothalamic neurons also controls the activity of the autonomic
nervous system; direct effects of leptin on ObRbcontaining
neurons in the brainstem and elsewhere may
also play an important role (31, 33).
ObRb is also expressed in multiple peripheral tissues,
including pancreatic islets, adipose tissue, skeletal muscle,
liver, and immune cells (36, 37, 42). In the pancreatic
islets, leptin directly inhibits insulin expression and secretion
(42). In liver and white adipose tissue, leptin inhibits
lipogenesis and stimulates lipolysis (36, 37) and adipocyte-specific
overexpression of ObRb prevents dietinduced
obesity (DIO) in mice (38). Leptin directly promotes
fatty acid oxidation in isolated adipocytes and skeletal
muscle (39, 40) and decreases lipid levels in isolated
livers (43). Liver-specific overexpression of ObRb prevents
hepatic steatosis in ObR-deficient fa/fa rats (44, 45).
However, deletion of the ObRb in these peripheral tissues
has no effect on energy balance, body weight, or glucose
homeostasis in mice, indicating that these processes are
Table 1.
Factors That Regulate Serum Leptin Levels
Factors Promoting Leptin Secretion
Excess energy stored as fat (obesity) a
Overfeeding a
Glucose
Amino acids
Insulin
Glucocorticoids
Estrogens
Inflammatory cytokines TNF- and IL-6 (acute effect)
Factors Inhibiting Leptin Secretion
Low energy states with decreased fat stored (leanness) a
Fasting a
Thyroid hormones
Free fatty acids and other lipid metabolites
Catecholamines and adrenergic agonists
Androgens
PPAR agonists b
Inflammatory cytokine TNF- (prolonged effect)
a Denotes major factor influencing leptin levels.
b Unlike animals, PPAR agonists in humans decrease leptin gene expression but increase sc fat mass, thus presenting a null effect.
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